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2023 Update: New Parkinson’s Disease Treatments in the Clinical Trial Pipeline

New Parkinson’s Medication on the Horizon

The development of potential new medications for Parkinson’s disease (PD) medications remains very active, with multiple new medications in various stages of research development that are aiming to treat and slow down PD.

In past blogs, we have reviewed the various mechanisms of action that are being studied to see if they result in successful slowing of disease progression.

These treatment mechanisms include:

Targeting abnormal alpha-synuclein aggregation.

• Increasing activity of GLP-1, a strategy which may block activation of immune cells in the brain
• Other strategies of decreasing inflammation in the brain
• Increasing the activity of the enzyme glucocerebrosidase to enhance the cell’s lysosomal or garbage disposal system
• Decreasing activity of the proteins LRRK2 or c-Abl to decrease neurodegeneration
• Improving function of the mitochondria – the energy-producing element of the nerve cell – to support the health of the neurons
• Increasing neurotrophic factors to enhance nerve survival
• Using cell based therapies to restore healthy nerves in the brain

Decreasing oxidative stress in the brain

Most of the compounds presented in prior blogs are continuing to be studied in various stages of clinical trials.

You can view these past blogs below:

• Neuroprotective strategies in clinical trials – 2020
• Neuroprotective strategies in clinical trials – update 2021
• Medications in clinical trials – 2022
• Therapies for non-motor symptoms in clinical trials
• Repurposed medications being studied for PD

Here are additional medications that we are keeping our eye on in 2023 and into 2024

You can read more about each of the clinical trials mentioned by following the links provided. Each is associated with an NCT number on clinicaltrials.gov,  a database of all the clinical trials for all diseases worldwide. Each link also provides the contact information for each trial if you would like to find out more about the possibility of participating in the trial.)

Decreasing activity of LRRK2

BIIB122: One compound that is successfully moving through the research pipeline is BIIB122. We previously reported on a Phase 1 study of a small molecule LRRK2 inhibitor known at the time as DNL151. The results of that study were published , and this molecule now called BIIB122, is being tested to see its efficacy in a much larger group of people.

Mutations (a change in the DNA sequence) in the LRRK2 (Leucine-rich repeat kinase 2) gene represent a common genetic cause of PD. LRRK2 plays several roles in the cell and mutations that increase its enzymatic activity are thought to cause neurodegeneration. BIIB122 is a small molecule that decreases the activity of LRRK2. The current study NCT05418673 is evaluating whether taking BIIB122 slows the progression of PD more than placebo in the early stages of PD. The study will focus on participants with specific genetic variants in their LRRK2 gene.

Butanetap : Buntanetap is a small molecule that suppresses the translation of DNA into messenger RNA of several neurotoxic proteins. This group of neurotoxic proteins produces insoluble clumps that accumulate in nerve cells, disrupting the cell’s normal function. One of these proteins is alpha-synuclein, which abnormally accumulates in PD.  In early studies, Buntanetap showed reduction of inflammation and preservation of axonal integrity and synaptic function. The current study NCT05357989 is designed tomeasure safety and efficacy of Buntanetap compared with placebo in participants with early PD.

Sulfuraphane : Sulfuraphane is an antioxidant, found in dark green vegetables such as broccoli and brussel sprouts. It is currently being studied NCT05084365 to see if it improves motor and cognitive function in PD.

Decreasing activity of the c-Abl kinase

IKT-148009 : IKT-148009 is a small molecule that decreases the activity of c-Abl, an enzyme that acts on a wide range of targets within the cell, supporting many different cellular functions. Research suggests that overactivation of c-Abl is a downstream effect of oxidative stress and may play a role in neurodegeneration in PD. There is also research to suggest that increased c-Abl activation correlates with alpha-synuclein aggregation. These findings and others led to the possibility that inhibiting c-Abl may be a helpful strategy in PD therapy. The current study NCT05424276 is investigating whether decreasing the activity of c-Abl in early, untreated people with PD is safe and tolerable, and whether it improves motor and non-motor features of the disease.

Cell-based therapy

Bemdaneprocel (BRT-DA01, previously known as MSK-DA01): A recently-completed Phase 1 study investigated the surgical transplantation of dopaminergic neuron precursor cells into the brains of people with PD. In an open label study (one without a control group) of 12 people, the treatment was found to be safe and well-tolerated. Transplantation of the cells was feasible and resulted in successful cell survival and engraftment. A phase 2 study is currently being planned for early 2024.

Decreasing inflammation

RO-7486967/selnoflast: – RO-7486967 is a small molecule that inhibits the NLRP3 inflammasome, a complex of proteins involved in inflammation that is thought to be overactive in PD. The current study NCT05924243 will investigate whether this molecule is safe and tolerable in early stages of PD.

New mechanism of action: Targeting cell death

KM819:  Apoptosis, a series of organized molecular steps that leads to programmed cell death, is a normal part of cell function.  When this system goes awry however, cells may die when they are not supposed to. KM819 is a small molecule inhibitor of Fas-associated factor1 (FAF1), a key regulator of cell death. It is being investigated to see if decreasing the process of cell death will protect neurons in PD. The current study NCT05670782 is testing this compound in both healthy adults and people with PD.

The Parkinson’s Hope List

We continue to thank Dr. Kevin McFarthing, a biochemist and person with Parkinson’s for his efforts in creating and maintaining  The Parkinson’s Hope List  — a collation of all the compounds that are being explored as new therapies for PD at all stages of the research pipeline and is updated frequently. It is an excellent source of information for those interested in the current state of PD research focused on new potential treatments. APDA was privileged to host Dr. McFarthing as a special guest on our broadcast entitled  Dr. Gilbert Hosts:Taking Research From the Lab to our Lives .

Dr. McFarthing and his colleagues put together a yearly review of the medications for Parkinson’s disease in clinical trials. The year 2023’s review can be accessed here . Dr. McFarthing and colleagues reported that as of January 2023, there were nearly 139 Parkinson’s therapies active in the clinical trial pipeline as registered on the www.clinicaltrials.gov website involving almost 17,000 participants. Of these drugs tested, 76 (55%) trials were focused on symptomatic treatment (STs), medications that attempt ameliorate the symptoms of PD; and 63 (45%) were disease-modifying therapies (DMTs), medications that attempt to slow the progression of the disease. The pipeline grew in the past year, with 35 newly registered trials (18 ST and 17 DMT trials). Most of these clinical trials (34%) are in Phase 1 (early-stage of clinical testing, primarily performed to assess for safety), while 52% have progressed to Phase 2 testing stage (mid-stage, performed in small numbers of people with PD to assess for efficacy), followed by 14% currently in Phase 3 (late-stage trials, performed in larger numbers of people with PD to assess for efficacy).

APDA proudly funds innovative work

APDA recently announced its newly-funded research grantees for the 2023-2024 academic year.  Our new pool of grantees are working on many of the strategies discussed above and will continue to push the field of PD research forward, introducing new ideas to the field and new possibilities in PD therapy.

Here are some examples:

• Dr. Nikhil Panicker is investigating the NRLP3 inflammasome. He is exploring whether reducing the activation of the inflammasome within microglia can protect neurons from accumulating alpha-synuclein in a cell model of PD.
• Dr. William Zeiger is studying the mechanisms by which the abnormal accumulation of alpha-synuclein cause thinking and memory problems in PD.
• Dr. Naemeh Pourshafie is studying the relationship between tau and alpha-synuclein, two proteins that abnormally accumulate in neurodegenerative diseases.  

We are so proud to help make this vital work possible!

Tips and takeaways

• There is hope in progress, with multiple treatment strategies in the PD research pipeline.
• Potential treatments are generally divided into two large categories: disease modifying therapies and symptomatic treatments.
• Mechanisms of action that are being studied to alter the progression of PD include: decreasing activity of LRRK2, decreasing aggregation of alpha-synuclein, decreasing oxidative stress in the brain, decreasing activity of c-Abl, introducing dopaminergic neurons into the brain, decreasing inflammation, and inhibiting programmed cell death.
• APDA supports essential research, bringing new ideas to fruition in the treatment of PD. Read more  about past work we have funded, and the projects that we are funding this year.
• We need your support in order to continue this extremely valuable research. Click  here  to make a donation.

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Faster ‘in a dish’ model may speed up treatment for parkinson’s.

Could result in personalized models to test diagnostic and treatment strategies

Kira Sampson

BWH Communications

A new model that allows scientists to rapidly create Parkinson’s disease in a petri dish using stem cells could provide personalized diagnostic and treatment methods, according to researchers at Harvard-affiliated Brigham and Women’s Hospital.

The study’s results are published in  Neuron .

Existing “Parkinson’s in a dish” models can effectively transform stem cells into brain cells, but not quickly enough to study patient-specific cellular pathologies to guide tailored treatment strategies. This is important because patients with Parkinson’s disease are diverse and a one-size-fits-all treatment strategy may not work for some patients. The Brigham research team’s technology not only enables the transformation from stem cells to brain cells to occur reproducibly within weeks instead of months, but also allows researchers to develop models that reflect the diverse protein misfolding pathologies that can occur in the brain in that timeframe.

Existing “Parkinson’s in a dish” models can effectively transform stem cells into brain cells, but not quickly enough to … guide tailored treatment strategies.

“We sought to assess how quickly we could make human brain cells in the lab that give us a window into key processes occurring in the brains of patients with Parkinson’s disease and related disorders like multiple system atrophy and Lewy body dementia,” said senior author  Vikram Khurana, chief of the  Movement Disorders Division  at BWH and principal investigator within the  Ann Romney Center for Neurologic Diseases  at BWH. “And, unlike previous models, we wanted to do this in a short enough timeframe for these models to be useful for high-throughput genetic and drug screens and easy enough for many labs to use across academia and industry.”

Parkinson’s disease is a progressive and degenerative brain condition. Individuals with the disease often struggle with slowed movement, tremors, muscle stiffness, and speech impairment, among other health complications. PD, along with other neurodegenerative conditions like Alzheimer’s disease, causes protein build-up in neurons, leading to protein misfolding and impaired cell function. Current PD therapies can alleviate some symptoms but do not address the root cause of the protein misfolding.

“The problem is that the way protein clusters form in PD looks different in different patients, and even in different brain cells of the same patient,” said Khurana. “This begs the question: How do we model this complexity in the dish? And how do we do it fast enough for it to be practical for diagnostics and drug discovery?”

To create this model, Khurana’s lab used special delivery molecules called PiggyBac vectors to introduce specific cellular instructions, known as transcription factors, to quickly turn stem cells into different types of brain cells. They then introduced aggregation-prone proteins like alpha-synuclein, which is central to the formation of protein clusters in PD and related disorders, in nerve cells. Using CRISPR/Cas9 and other screening systems, they identified diverse types of inclusions forming in the cells, some of them protective and some of them toxic. To prove relevance to disease, they used their stem-cell models to discover similar inclusions in actual brains from deceased patients. The work enables new approaches for classifying protein pathologies in patients and determining which of these pathologies might be the best drug targets.

While marking progress, the model has several limitations researchers aim to address. For one, it currently generates immature neurons. The researchers aim to replicate this model with mature neurons to model the effects of aging on the protein aggregates that form. While the new system can rapidly create both neurons and key inflammatory “glial” cells in the brain, the current paper only examines these cells individually. The team is now combining these cells to study the inflammatory responses to the protein aggregation process that might be important for PD progression.

The two lead authors on the study, both research fellows in the Department of Neurology at BWH, commented on the clinical applications already underway in the lab.

“In one key application, we are utilizing this technology to identify candidate radiotracer molecules to help us visualize alpha-synuclein aggregation pathologies in the brains of living patients we see in the clinic,” said co-first author  Alain Ndayisaba.

“This technology will pave the way for rapidly developing ‘personalized stem cell models’ from individual patients. These models are already being used to efficiently test new diagnostic and treatment strategies ‘in a dish’ before jumping into clinical trials so we target the right drug to the right patient,” said co-first author Isabel Lam.

Disclosures: Khurana is a co-founder of and senior adviser to DaCapo Brainscience and Yumanity Therapeutics, companies focused on CNS diseases. Co-authors Chee-Yeun Chung and Xin Jiang contributed to this work as employees of Yumanity Therapeutics. Toru Ichihashi and Yasujiro Kiyota contributed to this work as employees of Nikon Corp. Lam, Ndayisaba, Jackson Sandoe, and Khurana are inventors on a patent application filed by Brigham and Women’s Hospital related to the induced inclusion iPSC models.

Funding was provided by National Institutes of Health (NIH), Aligning Science Across Parkinson’s (ASAP), Michael J. Fox Foundation, New York Stem Cell Foundation, Multiple System Atrophy Coalition, and private donors.

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Masks Strongly Recommended but Not Required in Maryland, Starting Immediately

Due to the downward trend in respiratory viruses in Maryland, masking is no longer required but remains strongly recommended in Johns Hopkins Medicine clinical locations in Maryland. Read more .

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New Findings About Key Pathological Protein in Parkinson’s Disease Open Paths to Novel Therapies

Researchers find a potential new target for treating #Parkinsons disease. ›

A so-called pathological protein long associated with Parkinson’s disease has been found in a new study to trigger cells to increase protein synthesis, an event that eventually kills the subset of brain cells that die off in this neurodegenerative condition. Researchers from the Johns Hopkins University School of Medicine who conducted the study say the findings offer potential new targets for treating Parkinson’s disease, which affects about 1% of the U.S. population over age 60 and has no cure.

The findings were published Nov. 29 in Science Translational Medicine . “Parkinson’s disease has major impacts on quality of life for patients, but also for their caretakers and loved ones,” says study leader Ted M. Dawson, M.D., Ph.D., professor in the Department of Neurology and director of the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. “We hope that research like this will provide mechanistic, molecular-based therapies that can actually slow or halt the progression of Parkinson’s disease.”

Parkinson’s disease symptoms, including a variety of motor and cognitive deficits that worsen over time, result from the death of neurons that produce the chemical messenger dopamine. Current treatments with drugs such as L-dopa largely focus on replacing the dopamine lost when these dopaminergic neurons die.

Over the past two decades, researchers linked these cells’ death to the presence of a pathological form of alpha-synuclein, a normal protein that is abundant in brain tissue. However, how pathological alpha-synuclein causes dopaminergic neuron death has been unclear. To pin down its role, Dawson and his colleagues used proximity labeling coupled with mass spectrometry to identify proteins that might interact with pathological alpha-synuclein in both a mouse and a lab cell model of Parkinson’s neurons.

They identified 100 such proteins that overlapped between these two models. When the researchers grouped the proteins by function, they found the majority play roles in ribonucleic acid (RNA) processing and translation initiation — key processes used by cells to make new proteins.

Several of the proteins were already known to work with the mammalian target of rapamycin (mTOR), which has a dual role in both regulating protein production and breaking down proteins.

Experiments in mice genetically manipulated to over-express the pathological form of alpha-synuclein showed that it indeed caused cells to increase protein synthesis by activating mTOR.

This process was triggered, the researchers say, when the pathological alpha-synuclein bound to another protein, tuberous sclerosis complex 2 (TSC2), preventing it from connecting with yet another protein TSC1, that keeps mTOR in check.

Treating the genetically engineered mice with rapamycin, a drug that targets mTOR, not only prevented excessive protein production in mice with a condition like Parkinson’s disease, but also eased some of the slow, halting movements and weak grip strength that are hallmarks of Parkinson’s disease in people.

Dawson says it’s still unclear precisely how increased protein production might harm dopaminergic neurons — the proteins might clog up key cellular pathways, or specific proteins produced in excess might be harmful for cells. He and his colleagues plan to investigate that question in future research.

In the meantime, he says, the findings point toward new targets for treating Parkinson’s disease. Researchers may, for example, develop drugs that act like rapamycin — currently used as an anti-rejection and anti-cancer medication — but work specifically in the brain to save dopaminergic neurons, sparing patients unnecessary body-wide side effects. Or, it may be possible to target TSC2 to produce a similar effect.

Other Johns Hopkins researchers who contributed to this study are Mohammed Repon Khan, Xiling Yin, Sung-Ung Kang, Jaba Mitra, Hu Wang, Taekyung Ryu, Saurav Brahmachari, Senthilkumar Karuppagounder, Yasuyoshi Kimura, Aanishaa Jhaldiyal, Hyun Hee Kim, Hao Gu, Rong Chen, Javier Redding-Ochoa, Juan Troncoso, Chan Hyun Na, Taekjip Ha and Valina Dawson.

This study was funded by grants from the JPB Foundation and the Bumpus Foundation. To see a video about why cell parts look the way they do, click here .

What You Need to Know about the New Parkinson’s Biomarker

A recent study in the journal Lancet Neurology announced the discovery of new biomarker for Parkinson’s disease.  The assay, which targets a protein found in the nervous system called alpha synuclein, can detect the disease in both people with Parkinson’s and individuals not yet diagnosed or exhibiting symptoms of the disease, but who are at a high risk of developing it. 

The discovery emerged from the Parkinson’s Progression Markers Initiative (PPMI), a decade-long longitudinal study led by the Michael J. Fox Foundation for Parkinson’s Research (MJFF) with support from more than 40 other organizations. More than 1,400 participants, both with and without Parkinson’s, participated in the PPMI study.  

Irene Richard, MD , a professor of Neurology and Psychiatry at the University of Rochester Medical Center (URMC), was involved in the development and planning of the PPMI study in her role as senior medical advisor to MJFF, a position she held from 2008-2011.  Richard continued her work with the organization as a member of the scientific advisory committee and was the principal investigator for the Rochester site of the PPMI study, overseeing the enrollment, evaluations, and follow up the initial cohort of study participants. We asked Richard why this new finding is important and what it means for future research efforts.

Describe alpha synuclein and the role it plays in Parkinson’s disease.

Abnormalities in alpha synuclein, a protein normally found in the nervous system, is associated with damage to neurons. Aggregates of misfolded and clumping of alpha synuclein that accumulate in the nervous system have been considered a hallmark of Parkinson’s disease (PD), but until now have only been detectable post-mortem. This new assay enables the detection of abnormal alpha synuclein during a patient’s life–and years before the clinical features of the PD appear. 

While the assay was remarkably good at detecting PD pathology and doing it at very early stages, it did not pick up abnormal alpha synuclein in some patients with PD, mainly those with certain genetic forms of the disease. This provides support for the notion that there may be “subtypes” of PD that, while manifesting the same signs and symptoms, likely have differing underlying pathophysiology.  This aspect will facilitate the development of targeted therapies and precision medicine approaches.

Why is it important to diagnose Parkinson’s early?

To date, we have only been able to treat the symptoms of the disease. Since PD is a progressive, neurodegenerative disease, a major goal has been to develop an intervention that could slow, or even stop progression.  The sooner in the disease course one could do that, the better off the patient would be.  Of course, the “holy grail” would be to actually prevent the disease from taking hold in the first place. 

Traditionally, PD is diagnosed when patients develop the characteristic motor symptoms such as tremor and slowness.  However, we have learned that the disease process has already begun long before these motor symptoms even manifest. For example, we now know that patients may have what we refer to as “pre-motor” symptoms such as diminished sense of smell, constipation, and a sleep disturbance known as “REM behavior disorder” wherein patients act out their dreams.

It is likely that, even if an intervention that was able to slow disease progression was developed, by the time someone has motor symptoms it may be too late.  The disease process has silently been causing neuronal loss for years, the “horse is already out of the barn,” and saving the limited number of neurons left may not suffice.  In the event we discover a disease modifying intervention, the earlier it can be given, the more likely it is to be effective–which is why there has been such a push to find ways to detect the disease at its earliest stages.

What more needs to be done before this is widely used to screen for Parkinson’s disease? 

This is a first step, but it is a big one–think Neil Armstrong.  At this point, the assay has been used on spinal fluid, obtained through a lumbar puncture or “spinal tap”.  However, it seems only a matter of time before further developments and refinement will enable it to be performed on fluids more readily accessible, such as blood, saliva, nasal secretions or potentially using a skin biopsy. 

How will this discovery help advance new treatments?

This assay will enable us to establish objective endpoints for clinical trials of PD treatments, ensure study participants exhibit appropriate pathology, and detect therapy induced changes in their status.  All of these factors will significantly decrease the risk to industry to invest in the development of potential “blockbuster” therapies, including preventative agents, and increase the speed with which they can be developed, tested, and brought to market.

One of the great challenges has been to find a way to actually measure disease progression.  To date, we have relied on clinical measurements, using a standardized rating scale, which while validated is far from an ideal objective measure of progression.  This is, in part, because one of the rather unique aspects of the disease is that the clinical features vary among and within patients, are affected by symptomatic medications, and can fluctuate, even within the course of a day. 

We knew that we must find an objective way to measure disease progression in parallel with seeking an intervention that could modify it.  A lack of such a measure has resulted numerous clinical trials yielding results that were difficult to interpret.  Complex clinical trial designs were a step forward, but have not been able to compensate for the lack of an objective and reliable biomarker.  This assay represents a big step forward in meeting that need.

What does this discovery mean to the Parkinson’s research community?

I have spent my entire academic career at the University of Rochester and have focused on PD, both clinical care of patients and clinical research.  To witness the growth and be part of this worldwide effort has been inspiring and I am thrilled with this breakthrough. There is a unique sense of energy and commitment that comes from being part of something greater than ourselves—a collective desire by everyone involved to alleviate the suffering of those living with PD now, with the hope of a future in which the disease will be a thing of the past.  

For more information: Michael J. Fox Foundation for Parkinson’s Research–Breaking News: Parkinson's Disease Biomarker Found

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Parkinson's Drug Reduces Disease Markers in Breakthrough Trial

A novel therapy designed to clear toxic clumps of a protein thought to be responsible for Parkinson's disease has shown promise in early clinical trials .

Produced by the US biotechnology company Vaxxinity, the immunotherapy candidate codenamed UB-312 is the first treatment shown to be capable of reducing concentrations of alpha-synuclein (α-syn) in cerebrospinal fluid, marking a significant step forward in slowing – or even halting – the disorder's progress.

Though the results of the trial are yet to be published and peer reviewed, reports from company officials are optimistic, suggesting they're onto something big.

"What we see from our UB-312 program is the potential to change the whole conversation around Parkinson's treatment and prevention," says Vaxxinity's co-founder and executive chair Lou Reese.

"Our findings suggest UB-312 could transform Parkinson's care, offering hope for improved outcomes with a disease-modifying treatment. The future isn't decades away: today's Parkinson's patients may have hope for the near, not distant future."

Parkinson's disease is a neurodegenerative condition that progressively manifests in rigidity, tremors, and slow movement. Second only to Alzheimer's in prevalence, nearly a million people in the US have a diagnosis, a figure expected to surge by a further 200,000 by the end of the decade.

The disease's symptoms can be traced to the death of critical nerve cells in a region close to the brain stem that is indirectly involved in fine motor control . Though the initial triggers of this degeneration have only loosely been associated with potential genetic and environmental factors , a quarter of a century of investigation strongly implies α-syn plays a critical role in the progress of Parkinson's disease.

Produced to regulate communication between neurons, the protein has a sinister side once it accumulates in insoluble clumps, damaging components such as the mitochondria and disrupting the cell's typical balances.

Vaxxinity's novel therapy uses antibodies to target these toxic clumps, ignoring the dissolved proteins and leaving them to conduct their day-do-day business. A clinical trial conducted a few years ago involving 50 healthy volunteers proved the procedure to be generally safe, with relatively mild side effects.

In this latest randomized, double-blind trial on 20 patients diagnosed with Parkinson's disease, the antibodies were shown to bind exclusively to aggregated forms of α-syn. Analysis of the spinal fluid of those given UB-312 revealed a 20 percent drop in their usual α-syn aggregate levels, compared with a 3 percent decline in those who received a placebo .

Follow-up clinical testing on patients with detectable concentrations of UB-312-induced antibodies in their spinal fluid samples suggested the clearing of the protein clumps may improve movements necessary for daily living.

"Currently, there are no treatments that address the underlying conditions of Parkinson's, and we are very excited about this target engagement data," says senior vice-president of Vaxxinity research, Jean-Cosme Dodart.

"This provides us confidence that we are going after the right target and in a way that is statistically and clinically relevant to patients. There is new hope on the horizon."

Making it over that horizon still depends on additional comprehensive clinical trials continuing to demonstrate the therapy as a safe and effective means of improving the quality of life for Parkinson's patients.

With so few promising treatments in development, even small hopes can mean a lot to the increasing number of people facing the gradual loss of motor control in coming years.

A Potential Parkinson’s Treatment Has Promising Results

A small new trial published in the journal Nature Medicine describes what would be two firsts for Parkinson's disease, if they pan out: a diagnostic test and a potential immune-based treatment that works similarly to a vaccine. The research is still early, but researchers are excited by the prospect of advances for a disease that lacks good diagnostics and treatments.

The target of both innovations is alpha synuclein, a protein that takes an abnormal form in Parkinson's patients—aggregating in their brains and destroying nerve cells involved in motor and some cognitive functions. While researchers have long known that these proteins are involved in the disease, finding ways to measure and target them has not been easy.

The (potential) Parkinson's vaccine

The Florida-based biotech company Vaxxinity developed a vaccine, or what it calls an active immune medicine, to train the immune system to attack only abnormal versions of the protein—which are improperly folded—and not the regular forms. This would essentially help people's bodies treat themselves.

“The idea is that patients should recognize their own misfolded proteins, and it is personalized because their own immune systems are doing the work,” says Dr. Mark Frasier, chief scientific officer at the Michael J. Fox Foundation for Parkinson’s Research, which funded the testing part of the study.

The Parkinson's test

The new diagnostic test for Parkinson’s, which was initially developed by researchers at the University of Texas and later Amprion, uses samples of cerebrospinal fluid to measure a person's levels of abnormal alpha synuclein. If the U.S. Food and Drug Administration (FDA) grants it full approval, it will become the first test for diagnosing Parkinson's. (The FDA classified it as a breakthrough device in 2019, a status that expedites access to innovative technologies where there is unmet need.) “Without [such a test], you’re kind of shooting in the dark,” says Mei Mei Hu, CEO and co-founder of Vaxxinity.

Alpha synuclein has been tricky to measure in the body for several reasons, says Frasier. While everyone has the protein, abnormal forms of it occur in relatively small amounts, so they're harder to detect via imaging. This type of alpha synuclein also tends to clump inside cells rather than outside of them, making it even harder to see. If clumps are large enough to become detectable, they can look structurally similar to amyloid or tau—the proteins implicated in Alzheimer’s disease—so imaging tests might misdiagnose people with Alzheimer’s rather than Parkinson’s.

Read More : Michael J. Fox: Chasing Parkinson's Treatments

The test overcomes those hurdles by cleverly exploiting normal forms of the protein. Parkinson’s experts believe that tiny amounts of abnormal alpha synuclein circulate in the spinal fluid of patients, but are too small to be detected through imaging. To run the new test in the study, researchers take normal forms of the protein in the lab and add them to samples of spinal fluid from patients; that prompts any misfolded protein that might be present in the samples to pull the normal proteins into misfolded aggregates, amplifying the signal for the abnormal form. Scientists then use a fluorescent probe to detect how much antibody to the misfolded protein patients generated, resulting in a biomarker, or stand-in for the treatment effect.

This test would be a critical advance because it makes it possible to identify patients with abnormal alpha synuclein at the earliest stages of the disease, when treatments might be more effective.

With more data from patients, researchers hope to further refine what different levels mean, so that the test will be able to tell not just if a person has Parkinson's but whether someone might be at a greater risk of developing it. Currently the test is only used in research studies, but more results like these—as well as data on whether the same process can be applied to blood samples—could speed the test to getting approved for wider use.

What the study found

The Vaxxinity trial, which included work from researchers at the University of Texas, the Mayo Clinic, and the Michael J. Fox Foundation for Parkinson’s Research, included 20 people with Parkinson’s. It was just designed to test the safety of the approach, so the study only provided hints about the treatment's effectiveness. Everyone received three shots over nearly a year; some contained the treatment at different doses, and some contained a placebo.

Overall, people receiving the vaccine generated more antibodies against the abnormal alpha synuclein protein than those vaccinated with placebo, as measured by the Parkinson's test. Antibodies started to ramp up about four months after the vaccinations began.

Read More : Changing Your Diet and Lifestyle May Slow Down Alzheimer’s

“What is unique about our technology is that it can stimulate the immune system to produce very, very specific antibodies against toxic forms of alpha synuclein, and do it in a safe way, which is reassuring,” says Jean-Cosme Dodart, senior vice president of research at Vaxxinity and senior author of the paper.

According to the test results, about half of the patients in the trial showed high levels of antibodies against the misfolded alpha synuclein, and most of these patients received the highest dose of the vaccine. They also scored the highest on motor and cognitive tests. There were too few patients to adequately assess any changes of Parkinson’s symptoms, but the researchers believe that longer follow-up with those tests, and potentially more frequent or higher doses of the vaccine, could lead to improvements in those scores. “The results are very, very encouraging,” says Dodart.

“This paper demonstrates that in a small number of people, the vaccine is having an impact on misfolded alpha synuclein, which is really exciting,” says Frasier. “We are now in the biological era for Parkinson’s disease."

Correction, June 26

Correction, June 25

The original version of the story mischaracterized the roles of each of the groups involved in developing the Parkinson's test. It was developed by researchers at the University of Texas, who continue to use it for research purposes along with other academic groups; Vaxxinity did not directly help develop the test. Amprion is developing the commercial version of the test. It also misstated which groups that conducted the trial. Vaxxinity conducted the trial, with collaboration from other institutions; it was not conducted jointly by Vaxxinity, researchers at the University of Texas, the Mayo Clinic, and the Michael J. Fox Foundation for Parkinson’s Research.

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• Published: 19 April 2022

Redefining the hypotheses driving Parkinson’s diseases research

• Sophie L. Farrow   ORCID: orcid.org/0000-0002-6578-4219 1 , 2 ,
• Antony A. Cooper 3 , 4 &
• Justin M. O’Sullivan   ORCID: orcid.org/0000-0003-2927-450X 1 , 2 , 3 , 5  

npj Parkinson's Disease volume  8 , Article number:  45 ( 2022 ) Cite this article

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Parkinson’s disease (PD) research has largely focused on the disease as a single entity centred on the development of neuronal pathology within the central nervous system. However, there is growing recognition that PD is not a single entity but instead reflects multiple diseases, in which different combinations of environmental, genetic and potential comorbid factors interact to direct individual disease trajectories. Moreover, an increasing body of recent research implicates peripheral tissues and non-neuronal cell types in the development of PD. These observations are consistent with the hypothesis that the initial causative changes for PD development need not occur in the central nervous system. Here, we discuss how the use of neuronal pathology as a shared, qualitative phenotype minimises insights into the possibility of multiple origins and aetiologies of PD. Furthermore, we discuss how considering PD as a single entity potentially impairs our understanding of the causative molecular mechanisms, approaches for patient stratification, identification of biomarkers, and the development of therapeutic approaches to PD. The clear consequence of there being distinct diseases that collectively form PD, is that there is no single biomarker or treatment for PD development or progression. We propose that diagnosis should shift away from the clinical definitions, towards biologically defined diseases that collectively form PD, to enable informative patient stratification. N-of-one type, clinical designs offer an unbiased, and agnostic approach to re-defining PD in terms of a group of many individual diseases.

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Introduction.

There is growing recognition that Parkinson’s disease is not a single entity 1 , 2 . Rather there are multiple different clinical, genetic and epidemiologically heterogeneous diseases that together are recognised within the one umbrella term of Parkinson’s disease 3 , 4 , 5 . Hereafter we refer to the multiple diseases as ‘ PD ’ for simplicity, and to prevent clouding the literature with a new term. Despite growing recognition of this concept, the majority of PD targeted research focuses on the ‘common’-pathological end-point of a linear PD storyline 6 : the physical manifestation of neuronal inclusions termed Lewy bodies, and the loss of dopaminergic neurons (DAn) within the central nervous system (CNS). This focus on the end-point pathology has proven its worth in the development of effective symptomatic therapies that include Levodopa 7 . However, the failure of nineteen phase 3 intervention trials 8 targeting modification of disease progression illustrates a limitation of this focus. The restricted focus on endpoint pathology largely arises from issues including that PD diagnosis typically occurs many years after disease onset, predominantly on the basis of motor symptoms, and yet one can only study PD patients after this clinical diagnosis is made. The successful development of disease-modifying therapeutics has been further hindered by the absence of biomarkers, and more critically—the absence of informative, molecular mechanisms that define each of the individual disease s that collectively form PD. This is reflected in a lack of PD intervention trials that target specific mechanistic changes in groups of individual patients defined according to the mechanism(s) that contribute to disease development/progression. The SURE-PD3 trial is an exception that targeted only individuals with low serum urate concentrations 9 . However, beyond the SURE-PD3 trial, there is typically no specific measurable biological signal for the success of a disease-modifying intervention for each disease within the PD umbrella 10 . Instead, we remain reliant on relatively insensitive and variable clinical measures of PD progression 8 .

The advent of genome-wide association studies (GWAS) has enabled the identification of variants associated with risk of disease development 11 , different rates of cognitive decline 12 , and different rates of progression for PD 13 , 14 . However, the conglomeration of datasets needed to achieve the sample size and statistical power required for GWAS perpetuates the one-disease model of PD, and overlooks the presence of multiple different clinical, genetic and epidemiologically heterogeneous diseases. In these situations, the conglomeration of data across multiple different Parkinson diseases dilutes the frequency of specific disease-associated variants and thus reduces the ability to identify those variants that contribute to the trajectory of each individual disease (i.e., the aetiology). As such, the integration of genetic and standardised clinical data into a coherent coordinated approach to slow or prevent PD development, is yet to materialise. Achieving this requires that we move away from a dependence on the shared terminal pathology and clinical definitions and develop a means for patient stratification, using specific genetic information, that is based upon a sound understanding of the aetiology of each contributing molecular disease. But how can you achieve this, when to study the different diseases you must first define them? Here we will discuss how this circular argument can be broken using genetic, molecular and clinical information to identify the different trajectories within PD, from a prospective, disease risk-driven perspective, that stratifies patients and therapeutics without a priori assumptions.

Multiple disease trajectories beneath the Parkinson’s disease umbrella

In 2008, William Weiner wrote “there is no Parkinson disease” 1 and suggested Parkinson disease s as a more fitting term for the observed multiple aetiologies. The term Parkinson diseases is consistent with the fact that there is no obvious, predictable disease trajectory following diagnosis, even in monogenic forms of the disease. Rather, each individual’s pathway is unique, or at most shared with a limited number of fellow patients 15 .

To illustrate the impact that treating PD as a group of diseases with different but overlapping aetiologies 4 , 5 , 16 can have on our understanding of the disease, let us consider a conceptual model where each disease within PD is represented by a mountain within a range of mountains (Fig. 1 ). At present we are unable to accurately define the number of different diseases that collectively form PD, thus we have limited our model to seven mountains, for simplicity. In the PD mountain range model, an individual’s genetic risk is represented by the position in the valley (i.e., basecamp) where the individual starts climbing—this position naturally limits the mountain(s) that can be ascended and the route(s) that can be taken. PD patients cluster according to their basecamp, of which there are a limited number, defined by the potential and realised combinations of the risk variants within the genome. Environmental signals from the dynamic basecamp surroundings interact with the individual’s genetic factors to alter aspects of the disease, including onset age at which the patient begins climbing, or whether the individual even develops PD. These environmental signals include, among others: pesticides and pollutants 17 , 18 , diet 19 , viral infection 20 , head trauma 21 , inflammatory diseases 22 (for an in-depth review on the role of environmental signals in relation to PD genetics see Johnson et al. 23 ). Once an individual has begun ascending a mountain, the topology of the mountain, which represents the intrinsic (e.g. the gut microbiome 24 or comorbid disease pathology 25 ) and extrinsic (e.g. exercise 26 , diet 19 , and periodic fasting 27 ) factors, influences how quickly each individual climbs the route (i.e., the rate of disease progression), and thus the presentation and severity of symptoms 15 .

Conceptual model assimilating the different diseases within PD to mountains within a range. There are likely many more mountains (diseases) than presented in this conceptual model. The topology of the valley floor represents the total variation in interaction between age, environment, comorbidities, sex and genetics of the population. An individual’s genetic risk is represented by the position in the valley (i.e., basecamp) where the individual starts climbing. Different signals (environment, age, comorbidity) from the dynamic basecamp surroundings interact with the individual’s genetic factors to alter aspects of the disease including onset age at which the patient begins climbing, or whether the individual even develops PD (reflected in the pie charts at base camps). The topology of the mountain (e.g. intrinsic and extrinsic factors) affects how quickly each individual climbs the route (i.e., the rate of disease progression), and thus the range, presentation and severity of symptoms 15 . The small boxes (i.e., checkpoints) along the routes of ascent represent potential biomarkers that could be developed/used to provide an unbiased snap-shot that can be used to track disease development within individual patients. However, these ‘on route’ biomarkers will likely change over the course of the disease.

Individual diseases that together comprise PD are heterogeneous in and of themselves. This is represented in our model by the existence of multiple routes to each mountain summit. These routes are not independent, merging and diverging, meaning it is likely that individuals can switch between the routes dependent on their particular combination of intrinsic and extrinsic factors. Although heterogeneity likely exists within each disease, it would ideally be sufficiently homogeneous to provide a single therapeutic target for treatment development. Furthermore, each route has different markers, or checkpoints, at different stages—akin to the biomarkers that provide an unbiased snap-shot that can be used to track disease development within individual patients. It is important to note however that these ‘on route’ biomarkers will change over the course of the disease, and are likely to be influenced by the individual’s age, diet, and combination of predisposing comorbid diseases.

It can be argued that there are commonalities across individual diseases that contribute to PD (i.e., shared between the different mountains within the range). Treating these commonalities would provide treatment for a larger group of patients. This may be true. However, whilst potentially useful, treating these commonalities would have limited benefit, as the symptoms (e.g. resting tremor and bradykinesia) appear late in the disease course, and thus patients would be more disabled (closer to their respective summits) by the time the treatment is initiated. Notably, disease-modifying interventions that target PD based on this premise have yielded little success thus far.

Other models of PD have been presented before. Perhaps best known is William Langston’s elephant model 28 which captures the idea of diverse symptomology but still presents PD as a single disease, or, elephant. In our model, the elephant would be represented as a single mountain within the PD mountain range. Thus Langston’s model does not capture the multiple diseases that collectively form PD, or the heterogeneity that is inherent to each disease.

Using ‘omics to inform origins and trajectories of Parkinson’s disease

It is the patient’s combination of genetic risk coding (e.g. LRRK2 -G2019S or SNCA -A53T) and non-coding variants that initially “set the stage” and determine which basecamp and mountain an individual will start ascending in their journey towards PD. The application of GWAS to the study of PD enables unbiased population-level identification of the genetic basis of risk that exist long before the disease initiates. However, the genetic variants that have been associated with PD by GWAS (e.g. 90 genetic loci 11 ) only explain between 16-36% of the heritability of PD. Additionally, apart from a few exceptions, the odds ratios of the individual variants are typically low (e.g. between 0.8 – 1.2) 11 . Indeed, the current predictive ability of the SNPs associated with PD is so low as to make meaningful risk score prognosis unfeasible 29 . The missing heritability can partly be explained by issues with merging the multiple different diseases that contribute to PD, into the single entity that is defined by late-stage pathological markers (i.e., performing GWAS from the perspective of PD being a single disease). Furthermore, the reliance on a clinical definition means that no two ‘omics studies yield similar results since they only represent those of the heterogeneous patient population from which they were applied (e.g. 30 ). Averaging these different but related datasets results in the identification of only the most significant risk loci that are common across all the diseases reaching statistical significance. The issue of averaging signals across the heterogeneous diseases that contribute to PD, when undertaking a GWAS, can be addressed by stratifying PD patients according to their genetically defined start-point, in turn enabling selection of informative longitudinal biomarkers and effective therapeutic approaches (specific to each route). This stratification can be achieved through genomic approaches that explore the specificities of GWAS manifestation 31 , 32 , and inform the distinct routes of PD development. As such, GWAS-based patient stratification could indicate 1) which pathway(s) is dysregulated; 2) pathway biomarkers to be examined; and 3) which targets should be considered for therapeutic intervention. However, shifting from simply identifying GWAS signals to informative stratification requires in depth characterisation of the causative variant(s) function 33 .

Until recently 33 , our inability to functionally translate non-coding genetic variation and risk to biologically disease-relevant pathways has meant that the earlier stages of PD development have been primarily neglected as a means of stratification or therapeutic intervention. In contrast to the noncoding risk variants, coding mutations in GBA and LRRK2 genes have been explored and enabled patients with these specific mutations to be stratified for therapeutic intervention, targeting these genetic subgroups of patients 34 , 35 . Furthermore, Szwedo et al. demonstrated a role for APOE-ε4 and GBA mutations in the rate of cognitive decline in PD patients, but found no significant impact for common variants in SNCA and MAPT 12 . These findings raise the possibility for earlier identification and stratification of individuals at high risk of rapid cognitive decline, thus highlighting suitable candidates for future targeted trials. Despite progress, the known incomplete penetrance of these mutations is problematic 36 and highlights a remaining knowledge gap surrounding the mechanistic role of some of these mutations, such as the role of LRRK2 mutations in disease progression 14 . This therefore raises the question as to whether such interventions will be effective against disease progression even in patients with these specific mutations. Nonetheless, with recent advancements, our understanding of how both coding and non-coding risk manifests is evolving 33 , 37 . Such understanding can be used to inform hypotheses which will aid in the identification and stricter classification of individual diseases within PD that could also lead to targeted therapeutics.

Functional characterisation requires that the associated molecular, cellular and physiological phenotyping is sufficiently deep to allow accurate assignment of the causal variants and their target genes 38 , and potentially what tissue(s), the disease risk is conveyed in. Panyard et al. applied an approach to functionally characterise and assign the action of causal genetic variants in Alzheimer’s disease (AD) 39 . Briefly, Panyard et al. integrated genomic and clinical data from two longitudinal AD cohorts with epigenetic annotations to develop cell-type-specific genomic functional annotations 39 . These annotations were used to identify which SNPs are likely to be functional in different tissues 39 . The authors demonstrated that effects of these SNPs in the liver were statistically associated with Alzheimer’s diagnosis 39 . In so doing, Panyard et al. highlighted a potential contribution from the liver towards AD, including associations with core AD cerebrospinal-fluid biomarkers, in what is widely considered a ‘brain-centric’ disease. Whilst a small study ( n  = 79 AD patients), the finding that changes in the liver were predictive for some, but not all, individuals is consistent with the hypothesis that the liver malfunction accounts for one of the heterogeneous diseases that collectively contribute to AD 40 .

Genomic approaches are also being applied in attempts to identify and understand the cell- and tissue- types where genetic risk manifests in PD 41 , 42 . For example, Coetzee et al. 43 used histone modification data combined with enrichment analyses to demonstrate that many PD-associated genetic variants were enriched, and had expression quantitative trait loci (eQTL) associations, in non-neuronal cell-types, including lymphocytes, mesendoderm-, liver- and adipocyte- cells 43 . Similarly, we have used a discovery-based approach to identify putative regulatory impacts of non-coding PD-associated risk variants in both the CNS and peripheral tissues 33 , 44 . Notably, our analyses indicated that eQTL effects for a subset (28%) of the 90 PD-associated risk variants were only detected in peripheral tissues (e.g. thyroid and oesophagus) 33 while only 2% of PD risk SNPs had identifiable eQTLs solely in CNS tissues. Given that tissues are complex mixtures of cell types, the oesophageal finding does not imply that the effect is due to the muscles at the exclusion of the nerves that innervate the oesophagus. However, the finding is consistent with peripheral symptomology (e.g. dysphagia), that is sometimes observed in the early stages of PD 45 .

In an attempt to determine which tissues, and subsequently cell-types, are responsible for PD heritability, Reynolds et al. 41 used stratified Linkage Disequilibrium score regression 46 (see box 1 ) to measure the contribution(s) that common genetic variation makes to the heritability of PD across 53 tissues (inc. 13 brain region tissues), using schizophrenia as a comparative measure. In contrast to schizophrenia in which all 13 brain tissues were significantly enriched for heritability, there was no enrichment for PD heritability across any of the 53 tissues (in the CNS or peripheral tissues). The lack of PD heritability enrichment across these bulk tissues led Reynolds et al. to question whether cellular heterogeneity within tissues may be masking signals, and thus sought to investigate cell-type-specific enrichment of heritability. However, across 6 human and 30 mouse CNS cell-types, Reynolds et al. identified no cell-type enrichment for PD heritability. The Lewy Body pathology in specific neuronal cell types, associated with PD, has encouraged researchers to focus efforts towards understanding risk in neuronal subtypes. However, the findings from Reynolds et al. provide reason to believe that risk loci are affecting non-CNS cell-types and/or cellular processes and pathways across multiple cell types, and to which different cell types have varying vulnerability 41 . Such varying vulnerability, consistent with the proposed threshold theory for PD 47 , could likely be a result of interactions with environmental factors and/or comorbid disease pathology.

In contrast to the lack of cell-type heritability enrichment identified by Reynolds et al., there have been multiple studies to date that implicate glial cell types, mostly microglia, in neuroinflammation and PD pathogenesis 42 , 48 , 49 . Given these implications, Bryois et al. combined cell-type-specific gene expression and GWAS data to explore the role of glial cells in PD pathogenesis 49 . Roles for microglia were indicated by the finding that cell-type-specific ATACseq identified functional PD risk loci that were enriched for autophagy and lysosomal processes 50 , both of which have been previously implicated in PD 51 . Furthermore, elevated LRRK2 expression, associated with the linked PD GWAS SNPs rs76904798 and rs7294619 ( R 2  = 0.842), has also been shown to occur specifically in microglia 42 . Collectively, these data are consistent with the hypothesis that PD genetic risk variants affect non-neuronal cell types of the CNS. However, while these studies highlight the importance of cell-type consideration, they are still driven by a priori assumptions that are CNS focused. As such, it is essential to extend these analyses to non-CNS cell-types, following a more discovery-based, hypothesis-free approach, to determine if such risk enrichment is truly specific to the microglia, or if other non-CNS cell-types may also be involved in disease initiation and propagation.

Together these studies highlight how multiple ‘omics approaches can be used to identify the tissue- and cell-type-specific manifestations for GWAS risk variants. The findings we have discussed support two potential, non-mutually exclusive, hypotheses: First, the individual diseases within the PD umbrella may arise through genetic variation-dependent mechanisms that dictate the tissue-of-origin(s) and thus the pathological pathways associated with the disease. This concept is reflected in the mountain range model, with each basecamp representing a different, genetically-informed, start-point. In the second hypothesis, variants impacting a specific peripheral tissue- or cell-type, cause dysregulation that adds to the disease complexity/symptoms without necessarily leading to the CNS pathology that is typically associated with PD. This second hypothesis aligns with the threshold theory for PD which was developed on the basis of parallel degeneration of both the central and peripheral nervous systems 47 . As such, there is a need to look beyond the tissue- and cell-types that are traditionally associated with PD pathology to gain a greater understanding of the mechanisms through which genetic risk may be manifested. Advances within the fields of single-cell transcriptomics 52 , 53 and bulk-cell analyses 54 will provide additional insights that begin to untangle the relative contributions of genetics and the environment to PD risk manifestation. But the question remains, how do we apply these approaches to a mechanistically-heterogeneous disease?

Box 1 Glossary of terms.

Expression quantitative trait loci (eQTL): A genetic locus that affects (or correlates with) the expression (mRNA) of one or more genes.

Genome wide association study (GWAS): An approach used to associate specific genetic variations with particular diseases or traits. The genomes of individuals with the disease or trait of interest are compared to the genomes of matched, control, individuals – to identify variants that are significantly associated with that particular disease or phenotypic trait.

Infinitesimal model: A model built on the premise that the inheritance of a quantitative trait is controlled by an infinite number of loci, and each locus has an infinitely small effect.

Linkage disequilibrium (LD): The non-random association of alleles at different loci.

Linkage disequilibrium score regression (LDSC): A statistical method for quantifying the separate contributions of polygenic effects and various confounding effects, such as population stratification, based on summary statistics from GWA studies.

N-of-1 approach: In this context, an n-of-1 analysis is a meta-analyses of deeply characterised single patient information, of individuals within a heterogeneous cohort, that explores genetic variation in the context of the measured phenotype(s). In effect, the characteristics of each participant are individually (and frequently where possible) noted and contrasted to each other individual. This approach accounts for the individual-level heterogeneity that is present in PD.

Omnigenic model of complex disease: The model is centred on the premise that human genome regulatory networks are hugely interconnected, and almost any gene with regulatory variants in at least one relevant tissue will contribute to the heritability of the phenotype.

Single nucleotide polymorphism (SNP): The most common type of variation among people. One SNP represents a variation at a single position (i.e. nucleotide) in the DNA sequence.

Using big data to identify individual trajectories in a heterogeneous disease

Conglomerating data from different cohorts provides a large sample size (n) which is otherwise unachievable from a single-centre cohort. As such, conglomerated data provides much-needed statistical power to address particular hypotheses. Despite providing statistical power, the conglomeration of different PD cohorts unfortunately also highlights the lack of strict diagnostic criteria for PD and related diseases, with different cohorts often using different diagnostic criteria 30 . A further confounding problem, that affects diagnosis even at the level of a single clinician, is misclassification 55 . Such misclassification raises the problem of inclusion of non-PD patients in cohorts, which may be skewing outcomes of observational studies and clinical trials. A third, and substantial, complicating factor is the likely multiple different mechanistic diseases that exist within the ‘homogenous’ clinical PD cohorts currently studied. This problem is particularly prevalent in cohorts that include patients with different genetic predispositions to diseases within PD, such as GBA- PD and LRRK2- PD patients, who typically present with different symptomatic trajectories 56 , 57 . Grouping these different individual diseases together is likely causing a loss of information. If data conglomeration is to achieve what is hoped, disease biomarkers, and more specifically biomarkers for the different diseases that collectively form PD are urgently needed. The need to define individual diseases as opposed to merging them into a single entity is in line with the prediction made by Espay and Lang that smaller, smarter clinical trials are needed to move away from this ‘homogeneous’ clinical Parkinson’s phenotype 6 .

As discussed earlier, genetic risk variants offer an option for such genetic stratification—with an individual’s risk profile determining their disease starting point (e.g. specific basecamp in the mountain range model). These genetic risk variants, or SNPs, do not however act independently 33 . Rather they act in a combinatorial manner within a much larger genetic background. In order to understand the full contribution that PD-associated SNPs make to PD, they need to be considered in the context of the omnigenic 58 and infinitesimal 59 models for disease (see box 1 ), and in terms of network medicine 60 . Network medicine approaches enable the disease to be contextualised as a sum of inter-connected perturbations, reflective of the underlying genetic and molecular risk drivers (i.e. studying PD risk variants in the context of an individual’s complete genotype). The utility of network medicine 60 has being explored in other complex diseases, and has already aided in the identification of novel targets for therapeutic strategies and development 61 , 62 .

Exploring the impact and interconnectivity of genetic contributions to an individual’s disease risk profile, from a network medicine angle, has only become feasible following recent advancements. These include the reductions in costs for genome sequencing and computing 63 , and the development of machine learning approaches to detect complex patterns in genomes. Such advances have informed, and been enhanced by, the rapidly evolving post-GWAS genome-editing toolbox, including CRISPR screens 64 and massively parallel reporter assays 65 (to test observed patterns for functional significance). These tools will over time provide the data required to understand the complete genetic contributions to the development of the diseases that collectively form PD, amongst other complex diseases. Collaborative efforts, such as the Atlas of Variant Effects Alliance ( https://www.varianteffect.org/ ) 66 , will be critical in enabling the curation and systematic collation of results from these functional post-GWAS studies. Another recent technological advance that will likely enhance genomic findings from a phenotypic perspective is the introduction of wearables 67 . Such devices have been shown to provide vital sign data (e.g. heart rate and electrodermal activity) at a level equivalent to that gained in a clinical setting 68 . The widespread uptake of these wearables enables individualised, longitudinal and continuous health monitoring. While identifying signal from noise in movement measurements is challenging, combining the in-depth phenotypic data that wearables provide with matched genetic data promises to aid in identifying clinical differences amongst the different genomic diseases within PD.

Information on genetic variation and drug responses can be used to help determine which drugs, are likely to be safe and efficacious in an individual. These approaches are leading to the emergence of ‘genetically-informed’ clinical trials (i.e., precision medicine approaches) in PD 69 , 70 , 71 . For example, Ambroxol has been repurposed to treat PD patients with a GBA coding mutation 34 . Despite having only been trialled in a small, open label, non-randomised group of individuals, Ambroxol shows promise for the treatment of this well-defined yet heterogeneous (i.e., it included multiple GBA coding mutations) subset of individuals 34 . The Ambroxol trial is an exemplar that paves the way for future precision-informed clinical trials in PD. Not only does it address the issue of treating patients according to genomic information, but also shows the potential of repurposing already licensed medication 72 , to accelerate the process of drug development. The Ambroxol trial also included some idiopathic PD patients—of whom also showed promising responses to the treatment. Identifying idiopathic PD patients who specifically have reduced GCase activity (i.e., those with GBA modifying genotypes 30 , 44 ) may lead to better outcomes for patients.

Despite the obvious promise of a stratified approach to clinical testing and therapy, the lack of genotyping as a part of clinical assessment means that the identification of the relatively small numbers of individuals with genetic predispositions remains a major financial and temporal challenge. However, this is changing as initiatives, such as PD frontline ( https://pdfrontline.com/en ) and PD GENEration ( https://www.parkinson.org/PDGENEration ), are offering genetic testing for PD patients to ensure individuals carrying defined mutations are referred to the clinical trials best suited to them.

Concluding remarks & future perspectives

Recognising that many diseases contribute to PD highlights a challenge that is present in the search for a biomarker of PD progression and therapeutics. Specifically, if there are many diseases subsumed within the umbrella of PD, then we should be looking for biomarkers for each individual disease. That we continue selecting patients on the basis of clinical criteria rather than biological ones impairs our ability to do this. Even genetic risk for PD is currently viewed within the context of the shared pathology that connects the different Parkinson disease s . The utility of network medicine 60 has been established in other complex diseases, aiding the identification of novel targets for therapeutic strategies and development 61 , 62 . While it is certainly true that further initiatives involving large-scale data conglomeration will aid in the molecular and clinical understanding of the disease, the lack of uniformity in PD diagnosis and disease trajectories will likely confound findings from genomic and biomarker studies 30 , 73 . Recent initiatives (e.g. PREDICT-PD 74 and the Cincinnati Cohort Biomarker Program (CCBP) 75 ) that incorporate discovery-based analyses of prospective cohorts are seeking to address this by defining PD developmental pathways and biomarkers. Furthermore, we contend that it is time to consider systematic n-of-1 76 , 77 , 78 approaches (see box 1 ) in PD research, to identify the combinations and relative contributions of the genetic, pathological and environmental factors in each unique circumstance 3 , 79 , for individuals within a heterogeneous population. The population’s use of wearables will contribute to the collection of relevant data for achieving such an approach 80 . Ultimately, the aggregated results of n-of-1 approaches will help elucidate the many diseases that contribute to the one complex Parkinson disease. Redefining the hypotheses driving PD research will enable movement away from the current focus on shared pathology and clinical definitions. This in turn will make way for the development of targeted diagnostic and therapeutic approaches that are based upon a molecular understanding of the aetiology of the individual diseases, and thus have the ability to slow, stop or reverse disease progression and ultimately achieve disease prevention.

Reporting Summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.

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There is no data to share that is specific to this perspective paper. All information is included in the references.

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Acknowledgements

S.F., A.C., and J.M.O’S. were funded by the Michael J Fox Foundation for Parkinson’s research and the Silverstein Foundation for Parkinson’s with GBA—grant ID 16229 to J.M.O’S. S.F. and J.M.O’S. were funded by the Neurological Foundation—grant ID 3721588 (2008 SPG). S.F. was funded by the Dines Family Charitable Trust. A.C. received grant funding from the Australian Government.

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Farrow, S.L., Cooper, A.A. & O’Sullivan, J.M. Redefining the hypotheses driving Parkinson’s diseases research. npj Parkinsons Dis. 8 , 45 (2022). https://doi.org/10.1038/s41531-022-00307-w

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Recent developments in the treatment of Parkinson's Disease

Thomas b stoker.

1 John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK

2 Department of Neurology, Norfolk and Norwich University Hospital, Norwich, UK

Roger A Barker

3 Wellcome Trust – Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK

Parkinson’s disease (PD) is a common neurodegenerative disease typified by a movement disorder consisting of bradykinesia, rest tremor, rigidity, and postural instability. Treatment options for PD are limited, with most of the current approaches based on restoration of dopaminergic tone in the striatum. However, these do not alter disease course and do not treat the non-dopamine-dependent features of PD such as freezing of gait, cognitive impairment, and other non-motor features of the disorder, which often have the greatest impact on quality of life. As understanding of PD pathogenesis grows, novel therapeutic avenues are emerging. These include treatments that aim to control the symptoms of PD without the problematic side effects seen with currently available treatments and those that are aimed towards slowing pathology, reducing neuronal loss, and attenuating disease course. In this latter regard, there has been much interest in drug repurposing (the use of established drugs for a new indication), with many drugs being reported to affect PD-relevant intracellular processes. This approach offers an expedited route to the clinic, given that pharmacokinetic and safety data are potentially already available. In terms of better symptomatic therapies that are also regenerative, gene therapies and cell-based treatments are beginning to enter clinical trials, and developments in other neurosurgical strategies such as more nuanced deep brain stimulation approaches mean that the landscape of PD treatment is likely to evolve considerably over the coming years. In this review, we provide an overview of the novel therapeutic approaches that are close to, or are already in, clinical trials.

Introduction

Parkinson’s disease (PD) is a common neurodegenerative disease characterised by a movement disorder consisting of bradykinesia, rest tremor, and rigidity, along with postural instability, a range of other more-subtle motor features, and many non-motor features 1 . Many of the core motor features result from the loss of a specific population of neurons: the dopaminergic neurons of the substantia nigra pars compacta, which project axons to the striatum 2 , 3 . As such, most of the current pharmacological treatment approaches for PD aim to restore dopaminergic tone in the striatum.

Whilst often effective at improving motor function, current treatments are associated with significant side effects due to delivery of dopamine to extra-striatal regions, variability in their absorption and transit across the blood–brain barrier, and the non-physiological continuous release of dopamine and its effects on the dopamine receptors within the basal ganglia 4 , 5 . Patients frequently develop cognitive problems, levodopa-induced dyskinesias, and on-off fluctuations, which we have estimated to occur in 46%, 56%, and 100% of cases, respectively, at 10 years from diagnosis based on data from our ongoing community-based incident study in PD 6 , 7 . All of these factors coupled with some of the neuropsychiatric features of PD have a significant impact on quality of life in advancing PD. Many features of PD (such as cognitive impairment and autonomic dysfunction) have a mainly non-dopaminergic basis, resulting from neurodegeneration at other sites in the central nervous system as well as the enteric and autonomic nervous systems 3 , 8 . It is often these features that have the most detrimental impact on the quality of life of patients with PD, yet treatment options remain limited for these elements of disease.

Levodopa, the precursor of dopamine, was first developed for the treatment of PD in the 1960s and continues to be the most-effective therapeutic agent for PD in 2020 9 . Other dopaminergic drugs have since been used, including inhibitors of dopamine metabolism as well as dopamine receptor agonists, but these are generally less well tolerated and less effective. Thus, there is an urgent need for better therapies, including disease-modifying treatments. However, the requirement for relevant pre-clinical disease models for testing such agents and the lack of robust biomarkers for diagnosing PD and the identification of prodromal disease, which would allow for treatment before significant neuronal loss had occurred, pose barriers to drug discovery.

It is on this background that a number of new developments are emerging that may transform the management of PD over the coming years, and we will now discuss those that are in, or soon to be in, clinical trials ( Figure 1 ).

An expanding number of drugs are being considered for their ability to influence the pathogenic processes of PD. These include novel agents and technologies, such as active and passive immunisation and RNA interference techniques to limit the propagation, and synthesis, of α-synuclein. Additionally, several drugs used for other conditions are of interest for potential use in PD given their ability to influence pathways such as the lysosome–autophagy system, mitochondrial function, and neuroinflammation, for example. Abbreviations: α-syn, α-synuclein; ASO, anti-sense oligonucleotide; GCase, glucocerebrosidase; PD, Parkinson’s disease; RNA, ribonucleic acid; UDCA, ursodeoxycholic acid.

Immunotherapies

The pathological hallmark of PD is the presence of abnormal aggregates of α-synuclein 10 . The role of α-synuclein in PD is not clear, but it is presumed to play a central pathogenic role, as demonstrated by the fact that mutations or duplications/triplications of the gene ( SNCA ) cause rare familial forms of PD 11 , coupled with many independent studies showing the detrimental effects of manipulating α-synuclein in cell and animal models 12 , 13 . Potential pathogenic mechanisms of α-synuclein include dysfunction of vesicular transport, perturbations in the lysosome–autophagy system, mitochondrial dysfunction, and oxidative stress, for example 14 . It has also been proposed that pathological forms of α-synuclein can act in a prion-like fashion, allowing pathology to spread from cell to cell, and the “strains” underlying this are now being identified 15 . This in turn means the disease follows a pattern of pathology that results from the sequential involvement of a number of anatomical structures. All of this suggests that therapies designed to reduce levels of α-synuclein or the propagation of toxic “strains” may limit PD progression 8 .

One experimental approach to restricting the propagation of α-synuclein is to use antibodies to target and degrade extracellular α-synuclein and thus prevent it from “infecting” neighbouring cells. Passive and active immunisation techniques against α-synuclein have been shown to convey neuroprotective effects in animal models, with the results of early clinical trials in humans starting to emerge 14 . Other approaches to reducing α-synuclein levels include anti-sense oligonucleotide and ribonucleic acid (RNA) interference techniques to reduce its synthesis, though these remain in pre-clinical stages and are thus not discussed in detail here 16 – 18 .

A humanised monoclonal antibody targeting the C-terminus of aggregated α-synuclein (prasinezumab or PRX002, Prothena) has been shown to reduce free serum α-synuclein by approximately 97% and to be well tolerated in phase I clinical trials 19 , 20 , with a phase II trial currently underway ( {"type":"clinical-trial","attrs":{"text":"NCT03100149","term_id":"NCT03100149"}} NCT03100149 ). Another antibody, BIIB054 (Biogen), targeting the N-terminal portion of α-synuclein reduces the propagation of α-synuclein pathology and improves the motor phenotype in a PD model involving injection of α-synuclein pre-formed fibrils into mice 21 . This antibody has also been found to be well tolerated in humans 22 and is under investigation in a phase II clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT03318523","term_id":"NCT03318523"}} NCT03318523 ).

The company AFFiRiS are approaching this problem in a different way by investigating a range of treatments consisting of α-synuclein fragments or α-synuclein-mimicking epitopes designed to induce an active immune response against α-synuclein, with phase I trials completed ( {"type":"clinical-trial","attrs":{"text":"NCT01568099","term_id":"NCT01568099"}} NCT01568099 and {"type":"clinical-trial","attrs":{"text":"NCT02267434","term_id":"NCT02267434"}} NCT02267434 ). These products have been administered subcutaneously in early trials and seem to be well tolerated. One of these, AFFITOPE PD01A, conveyed a dose-dependent immune response to the peptide itself and to α-synuclein and is now being taken forward to phase II trials 14 .

The use of immunotherapies to limit the propagation of PD pathology is an interesting avenue for further exploration, but important questions remain, not least the extent to which PD in the clinic is driven by protein spread. In addition, the ability of these antibodies to cross the blood–brain barrier and influence α-synuclein homeostasis in the brain is potentially an obstacle for their use in the clinic. Furthermore, neuroprotective effects of such immunotherapies appear in part to be due to intracellular effects, and their ability to enter cells may influence their efficacy. Engineered fragments (intrabodies and nanobodies) may allow for greater central nervous system penetration and entry to the cell, but these are yet to enter clinical trials 23 . Another concern is the potential consequences of suppressing the physiological function of α-synuclein, an abundant protein whose function is incompletely understood. Suppression of α-synuclein levels in some models has been shown to be detrimental 24 – 27 , and evaluation of the long-term safety of this approach will be important. It is for this reason that some groups have sought to reduce α-synuclein through drug therapies, including the repurposing of β-agonists (see below).

Drug repurposing

An alternative approach to limit PD pathology and disease progression is through the use of drugs that reduce α-synuclein pathology or have beneficial effects on other processes implicated in PD ( Table 1 ). In particular, there is a great deal of interest in drug repurposing (using established drugs for a new indication), which would potentially lead to an expedited path to the clinic, given that safety and pharmacokinetic data may already be available. Here we discuss some of the most promising agents being considered for the treatment of PD ( Figure 1 ).

Abbreviations: ATP, adenosine triphosphate; G-CSF, granulocyte colony-stimulating factor; GLP-1, glucagon-like peptide-1; HSP90, heat shock protein 90; PGK1, phosphoglycerate kinase-1; Treg, regulatory T cell; UPDRS, Unified Parkinson’s Disease Rating Scale.

One class that is under consideration, but yet to enter clinical trials, is the β-adrenergic receptor agonists, given recent epidemiological and in vitro work demonstrating an association with reduced α-synuclein levels and risk of PD, thought to be mediated through modulation of SNCA transcription 28 . Given that such agents are widely used in the treatment of reversible airway obstruction, and have been for many years, moving this to the clinic should be relatively straightforward.

Of those that have gone to clinical trials, the glucagon-like peptide-1 (GLP-1) analogue exenatide, which is used for the treatment of type two diabetes mellitus, has advanced the most. This agent has been trialled in PD patients after a similar compound (exendin-4) was found to convey neuroprotective effects in cell and animal models of nigral degeneration 29 – 31 . Several mechanisms have been proposed to mediate this effect through GLP-1 receptor activation, including inhibition of apoptosis, reduced microglial activation and neuroinflammation, reduced oxidative stress, and promotion of neurogenesis 32 . In an initial open-label trial, exenatide was found to be safe in PD patients (though some experienced problems with weight loss), and there was an associated improvement in cognitive and motor function, which persisted after cessation of treatment 33 . This was followed by a double-blind randomised placebo-controlled trial, which reported that once-weekly exenatide was associated with a reduction in Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores in comparison to the placebo group 40 . A multicentre phase III trial is currently in set-up, in which participants will receive weekly exenatide or placebo ( {"type":"clinical-trial","attrs":{"text":"NCT04232969","term_id":"NCT04232969"}} NCT04232969 ). A pegylated form of exenatide (NLY01), which harbours enhanced pharmacokinetic properties, has also recently been taken to a phase I trial in healthy volunteers, with results awaited ( {"type":"clinical-trial","attrs":{"text":"NCT03672604","term_id":"NCT03672604"}} NCT03672604 ).

Another repurposed drug that has been trialled for PD is nilotinib. This is an ABL tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukaemia. ABL activity inhibits the activity of Parkin, which is important in the initiation of mitophagy, and nilotinib is proposed to enhance autophagy activity, potentially reducing the accumulation of α-synuclein aggregates 34 . An initial phase I trial reported that the drug was well tolerated and safe, with preliminary reports of benefits on motor and cognitive function 43 . However, there was no placebo group in this study, and some of the clinical effects observed may have been due to baseline differences between the groups and withdrawal of monoamine oxidase inhibitors in a number of subjects 44 . Nevertheless, nilotinib has now progressed to randomised placebo-controlled trials ( {"type":"clinical-trial","attrs":{"text":"NCT03205488","term_id":"NCT03205488"}} NCT03205488 and {"type":"clinical-trial","attrs":{"text":"NCT02954978","term_id":"NCT02954978"}} NCT02954978 ), and it appears to reduce the ratio of pathogenic oligomeric α-synuclein to total α-synuclein in the cerebrospinal fluid (CSF) 45 . However, a recent press release for the NILO-PD trial showed that, while safe and tolerable, nilotinib did not offer any clinical benefit.

Terazosin, an α 1 -adrenergic antagonist used in benign prostatic hypertrophy, has recently emerged as a putative treatment for PD. Terazosin has been found to activate phosphoglycerate kinase-1 and the chaperone protein HSP90, which is involved in multiple intracellular stress responses 46 . It has been shown to have neuroprotective effects in neurotoxin models of nigrostriatal degeneration in invertebrates and rodents, including after delayed administration 35 . Additionally, terazosin reduced α-synuclein levels in transgenic mice and in neurons derived from patients with LRRK2 mutation-associated PD 35 . Furthermore, a retrospective epidemiological study found that people taking terazosin have a reduced relative risk of PD 35 . These promising findings have led to terazosin rapidly progressing to a randomised placebo-controlled trial, which will involve 20 patients with Hoehn and Yahr stage 3 PD ( {"type":"clinical-trial","attrs":{"text":"NCT03905811","term_id":"NCT03905811"}} NCT03905811 ). However, terazosin reduces blood pressure and can cause orthostatic hypotension, which is a problem in many patients with advancing PD and may limit its applicability in this disease.

In addition to targeting α-synuclein clearance pathways, drugs that target other intracellular pathways may be useful in PD. For example, ursodeoxycholic acid (UCDA), a drug used to treat primary biliary cirrhosis, has been found to restore mitochondrial function in cells derived from patients carrying PARKIN and LRRK2 mutations as well as in invertebrate and rodent models of PD 47 – 49 . UCDA has recently progressed to a randomised placebo-controlled phase II trial, which is currently in the process of recruiting 30 patients with early PD ( {"type":"clinical-trial","attrs":{"text":"NCT03840005","term_id":"NCT03840005"}} NCT03840005 ). A number of other agents are currently in, or have recently completed, clinical trials, which are summarised in Table 1 .

Advances in our understanding of pathogenic subtypes of PD may allow for the targeting of specific pathogenic mechanisms in subgroups of PD patients. One such group is patients carrying GBA1 mutations, found in approximately 5% of so-called sporadic PD patients 50 – 52 . The GBA1 gene encodes the lysosomal enzyme glucocerebrosidase, the activity of which has been found to be reduced in PD patients without GBA1 mutations, making it an interesting therapeutic target for a wider PD population. These mutations are associated with dysfunction of the lysosome–autophagy system, important in α-synuclein clearance 53 , 54 . Some GBA1 mutations have been shown to lead to misfolding of glucocerebrosidase, which impairs its delivery to the lysosomal compartment, leading to perturbations in α-synuclein processing 54 . Ambroxol, historically used as an expectorant, has recently been trialled in patients with GBA1 mutation-associated PD, as it has been shown to facilitate the re-folding of glucocerebrosidase and increase its activity in human cells and transgenic mice with subsequent reduction in α-synuclein levels 55 , 56 . The results of the first open-label clinical trial of ambroxol in PD patients with and without GBA1 mutations (AiM-PD) have recently been published, where the drug was found to be well tolerated over 6 months, with an associated rise in CSF glucocerebrosidase levels 57 .

Alternatively, the glucocerebrosidase pathway may be targeted through glucosylceramide synthase inhibitors, which reduce levels of the glucocerebrosidase substrates glucosylceramide and glucosylsphingosine. Such substrate reduction therapies have been used in Gaucher disease (caused by biallelic mutations in the GBA1 gene), but the role of these substrates in PD pathogenesis is disputed 58 . A phase II clinical trial of a glucosylceramide synthase inhibitor (venglustat) in PD patients with GBA1 variants is currently underway (MOVES-PD, {"type":"clinical-trial","attrs":{"text":"NCT02906020","term_id":"NCT02906020"}} NCT02906020 ).

Targeting non-dopaminergic neurotransmitter systems

Though many of the motor features of PD are dopamine responsive, for others, such as freezing of gait and tremor, dopamine offers little benefit. It is now understood that deficiencies in other neurotransmitter systems underlie some of these features 59 . As such, there is interest in modulating their function to treat specific dopamine-resistant aspects of PD.

One novel drug that has recently received approval for use in PD is safinamide, a drug that is proposed to have multi-modal actions. It is a potent reversible monoamine oxidase B inhibitor, conveying a benefit for the treatment of dopaminergic aspects of PD. It also modulates glutamate transmission, which may be implicated in some of the non-motor features of PD 60 , 61 . In a multicentre phase III clinical trial involving 669 patients with moderate to advanced PD, safinamide resulted in improved UPDRS motor scores, reduced off-time, and improvements in depression and communication scores 62 . Safinamide is now becoming more widely available for clinical use, though its exact role is yet to be determined. Currently, it is most likely to be used as an adjunct to levodopa-based therapies, particularly in those who experience problematic dyskinesias and fluctuations.

Additionally, the cholinesterase inhibitors rivastigmine and donepezil have been trialled for their ability to reduce falls in PD, with promising preliminary results 63 , 64 . The noradrenaline reuptake inhibitors methylphenidate and atomoxetine are also currently being investigated for their effects on balance and gait in PD in an ongoing trial ( {"type":"clinical-trial","attrs":{"text":"NCT02879136","term_id":"NCT02879136"}} NCT02879136 ). Serotoninergic neurons in the dorsal raphe nucleus have been proposed to contribute to levodopa-induced dyskinesias, and the use of serotonin agonists has been seen to reduce such dyskinesias in animal models 65 – 67 . However, their use has been accompanied by worsening of other motor features of PD in some clinical studies 68 . However, advances in our understanding of the role of the serotoninergic system in the development of levodopa-induced dyskinesias means that there is ongoing interest in modulation of this system as a therapeutic option 69 .

Neurotrophic factors

Neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) have beneficial effects on dopaminergic neurons in pre-clinical models, and there has been much interest in developing neuroprotective therapies based on these 70 , 71 .

Open-label studies of intraputaminal GDNF infusion have seen improvements in motor UPDRS scores 72 , 73 , with some evidence of restoration of the nigrostriatal pathway pathologically and on imaging 74 . However, randomised double-blind trials have failed to recapitulate these results, including a recent study in the UK 75 , 76 . However, there has been much discussion about why these open and double-blind studies have produced such varying results, which led to a workshop in 2019 where these issues were addressed; the conclusions of which have recently been published 77 . Whilst GDNF studies have thus far yielded mixed results, this remains an exciting experimental approach with ongoing interest. Variable results in these trials may in part be due to the involvement of patients with moderately advanced PD, inadequate follow-up times, and the large placebo effect (which is often seen in clinical trials for PD).

Neurturin, a GDNF analogue, has also been trialled in patients, with similar results to those seen with GDNF, namely promising open-label trials that have failed to translate to clinical benefit in larger trials 78 – 81 . Nevertheless, determination of the most-appropriate patients, improvement in delivery systems, and development of novel neurotrophic factor analogues mean that this approach remains an avenue of interest and is currently being explored in a new EU-funded trial looking at cerebral dopamine neurotrophic factor (CDNF, Herantis Pharma). It has recently been reported in a press release that the agent can be delivered without major side effects, although it is too early to say whether it has therapeutic benefits for patients.

Regenerative treatments

As well as the pharmacological approaches described above, there is considerable interest in the use of cell-based and gene therapies to replace the function of the lost dopaminergic neurons. The aim of these treatments is to restore dopaminergic tone in a more targeted and physiological manner than can be achieved with current dopaminergic therapies. Several of these approaches are now entering clinical trials 82 .

Gene therapies may be used to increase dopamine levels in the striatum through the introduction of genes that mediate dopamine synthesis. Tyrosine hydroxylase (TH) is needed for the production of the dopamine precursor levodopa, which in turn is converted to dopamine by DOPA decarboxylase, also termed aromatic L-amino acid decarboxylase (AADC). Two gene therapies involving the genes encoding these enzymes are currently undergoing clinical trials for PD.

Voyager Therapeutics have developed an adeno-associated virus (AAV) therapy containing the gene for AADC (VY-AADC). This therapy has entered a phase I clinical trial, in which 15 patients with advanced PD are receiving the treatment at three different doses. It is introduced into the putamen, with preliminary reports suggesting that the treatment is well tolerated. The effects seem encouraging, particularly given that the volume of agent delivered covers a large part of the target structure (the putamen), with corresponding increases in enzyme activity. These benefits correlated with a dose-dependent reduction in levodopa dose 83 . A randomised sham-surgery controlled phase II trial is also ongoing ( {"type":"clinical-trial","attrs":{"text":"NCT03562494","term_id":"NCT03562494"}} NCT03562494 ).

A tricistronic lentivirus vector is also currently undergoing clinical trials. This treatment consists of the genes encoding AADC, TH, and GTP cyclohydrolase 1 (which catalyses the rate-limiting step of tetrahydrobiopterin synthesis, a cofactor required for the synthesis of dopamine and serotonin). The first iteration of this treatment to enter trials, OXB-101 or ProSavin®, was assessed in an open-label phase I trial involving 15 patients with advanced PD 84 . The treatment was well tolerated, with no serious adverse effects related to the treatment, with improvements in “off” state UPDRS scores at 12 months. However, the extent of improvement was not sufficient to make this therapy competitive. However, an improved version of this gene therapy with greater potency, OXB-102 or AXO-Lenti-PD, is currently in a two-part clinical trial in which safety will be assessed at multiple doses before progression to a randomised double-blind trial ( {"type":"clinical-trial","attrs":{"text":"NCT03720418","term_id":"NCT03720418"}} NCT03720418 ).

Cell-based therapies offer another emerging approach for the targeted replacement of dopamine to treat the dopamine-dependent aspects of PD. Cell-grafting with human foetal ventral mesencephalon has been taking place since the 1980s, and whilst this has been seen to be effective in some cases with patients able to come off dopaminergic medication for sustained periods, it has become clear that logistical barriers regarding the supply of adequate tissue will prevent this from ever being a useful treatment in itself 85 – 88 . Nevertheless, a renewable source of dopaminergic cells would make cell-based therapies potentially feasible, assuming they can be shown to have sustained clinical benefits to patients.

Stem cells offer a renewable source of dopaminergic neuron progenitor cells that can be grafted into patients, and clinical trials of such products are now underway ( Table 2 ). Whilst controversial trials involving parthenogenetic stem cell-derived neural stem cells have been ongoing for several years 89 , new stem cell products developed on the back of robust pre-clinical data are now progressing to trials 82 . A clinical trial of dopaminergic progenitors derived from induced pluripotent stem cells (iPSCs) has begun (Center for iPS Cell Research and Application, Kyoto University, Japan). In this trial, seven patients will receive bilateral grafts of allogenic iPSC-derived cells. Trials involving embryonic stem cell (ESC)-derived cells are underway in China ( {"type":"clinical-trial","attrs":{"text":"NCT03119636","term_id":"NCT03119636"}} NCT03119636 ) 90 and in set-up in the USA (NYSTEM-PD) and the UK/Sweden (STEM-PD trial). A number of other trials using ESC-derived neurons and allogenic and autologous iPSC-derived neurons are expected to commence over the next 2 to 3 years.

Abbreviations: ESC, embryonic stem cell; FDA, US Food and Drug Administration; iPSC, induced pluripotent stem cell.

Advances in deep brain stimulation

Deep brain stimulation (DBS) is another established treatment for PD that is useful in treating dopamine-dependent motor symptoms when levodopa-induced side effects become particularly problematic. DBS involves the surgical implantation of electrodes that stimulate subcortical structures including the subthalamic nucleus and globus pallidus internus 91 – 94 . DBS offers significant improvements in motor symptoms and fluctuations in comparison to best medical therapy in some advanced PD patients, but dopamine-resistant symptoms other than tremor (e.g. gait disturbance and postural instability) respond poorly 95 . It has also been suggested in an open-label trial that DBS is beneficial in early PD patients, with improved tremor scores and reduced development of de novo tremor 96 . In addition to surgical complications, DBS strategies may cause cognitive and neuropsychiatric adverse effects as well as speech dysfunction. Novel DBS approaches, including adaptive DBS, targeting different regions, and refined intra-operative imaging techniques promise to offer improved clinical applicability and reduce the impact of adverse effects 97 .

The pedunculopontine nucleus has recently been trialled as a new target for DBS, particularly for the gait problems seen in PD. While initial trials reported positive impacts on gait and postural instability, more rigorous subsequent trials were less promising, in part because of variability in the anatomical definition of the pedunculopontine nucleus in the human brain, suboptimal programming settings, and low patient numbers 61 , 98 . More recently, stimulation of the substantia nigra reticularis has shown promising effects on axial symptoms in preliminary studies 99 along with stimulation of the basal forebrain (with STN) for some of the cognitive deficits in PD 100 . In another pilot study, thoracic spinal cord stimulation significantly reduced the frequency of freezing episodes in patients with advanced PD, with trials ongoing 101 .

There is great interest in adaptive DBS, a system in which the stimulation delivered to the target is adjusted in response to physiological signals 61 . This approach theoretically limits adverse effects, improves clinical response, and reduces the requirements for battery changes and the associated cost. Further work is required in identifying and validating a reliable host signal 102 , but it is hoped that such technologies will enhance the clinical utility of DBS in the future. Non-invasive DBS techniques involving the use of external devices delivering electric fields to deep structures would circumvent the need for neurosurgery and its associated risks 103 . One such approach that has been used more for patients with essential tremor than PD involves using magnetic resonance imaging-focussed ultrasound lesioning of discrete brain structures. Reports on the long-term efficacy of these therapies are awaited 104 .

A wide variety of experimental treatment approaches for PD have progressed towards the clinic over recent years. Many previous putative treatments have fallen by the wayside when taken to clinical trials, despite being backed up by promising pre-clinical results, emphasising the need for robust trial design. A greater understanding of the pathogenic mechanisms and anatomical basis for PD symptoms has opened up avenues for new treatment modalities, and it now seems probable that the management of PD will evolve significantly over the coming years.

[version 1; peer review: 2 approved]

Funding Statement

The authors acknowledge financial support from the following organisations: Medical Research Council and Wellcome Trust Stem Cell Institute (Cambridge 203151/Z/16/Z), National Institute for Health Research (NIHR) (NF-SI-0616-10011), NIHR Biomedical Research Centre (reference number 146281), and the Cure Parkinson’s Trust. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Editorial Note on the Review Process

F1000 Faculty Reviews are commissioned from members of the prestigious F1000 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 (any comments will already have been addressed in the published version).

The referees who approved this article are:

• Fredric P. Manfredsson , Parkinson's 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.

Queensland researchers target gut health to slow or stop progression of Parkinson's disease

Australian researchers are working on developing drugs that target bugs in the guts of Parkinson's disease patients in a radical new treatment approach they hope will slow or even stop the progression of the debilitating illness.

Queensland University of Technology neuroscientist Richard Gordon said the research followed emerging evidence suggesting the gut was as important as the brain in the development of Parkinson's.

Associate Professor Gordon, based at the Translational Research Institute in Brisbane, said studies showed differences in the complex gut ecosystems of Parkinson's disease patients compared with healthy people.

He said people with Parkinson's disease were known to experience persistent inflammation and activation of the immune system, believed to be closely linked to an imbalance of microbes in their guts.

"The inflammation, over a prolonged period, has been shown to damage the vulnerable dopamine-producing neurons that are gradually lost in people with Parkinson's," Associate Professor Gordon said.

Two years ago, Ross Martin began to notice a tremor in his hand. 

The 66-year-old Queenslander is not the first in his family to be diagnosed with Parkinson's — his uncle also had the disease. 

"Being on a computer, you go to play a game or something [and] your left hand is hitting all the wrong keys," he said. 

"It's the little things at the moment, but the longer-term things and knowing where I'm heading and what life I'm heading towards is something I don't want to think about too much."

He said the the study gave him hope. 

"We are pro-science, and it's obvious the good work is being done," Mr Martin said. 

Rise in cases linked to 'chemical exposure'

Parkinson's disease is a progressive movement disorder, characterised by degeneration of dopamine-producing neurons in the brain.

The decrease in dopamine levels results in impaired mobility – including tremors, stiffness of the arms and legs, slow movement, and poor balance.

Other symptoms can include an impaired sense of smell, disturbed sleep, anxiety and depression, fatigue, gut problems, and speech changes.

Drug treatments, such as levodopa, which increases the amount of dopamine in the brain, help alleviate some patients' symptoms rather than slow the progression of the illness.

In what he described as "a radical new way of thinking" about Parkinson's disease, Associate Professor Gordon's team has been awarded $4 million over four years by the US Department of Defense to work on new therapeutics targeting the gut microbiome.

He said military personnel were considered at increased risk of developing neurological conditions, such as Parkinson's disease, because of chemical exposures during their service.

"There is this rapid increase in the prevalence of Parkinson's globally," Associate Professor Gordon said.

"We believe it's linked to … chemical exposures."

The gut is a new target

The Queensland research will involve both human and animal studies to identify new classes of therapeutics to treat Parkinson's disease, first described more than 200 years ago by London doctor, James Parkinson.

Scientists will study blood, urine, and faecal samples from at least 70 Parkinson's patients and compare them to those of similarly aged healthy volunteers.

"One of the ways we study the gut microbiome is by sequencing the bacteria that's present in people's guts," Associate Professor Gordon said.

They hope to be able to identify so-called "healthy bugs" that may disappear in people with Parkinson's.

"Then we're going to use that knowledge to develop drugs, or improve the drugs that we have, to target the microbes rather than just target the brain, which we've done in the past," Associate Professor Gordon said.

'Bugs as drugs'

In what he termed a "bugs as drugs" approach, he said the team would also engineer bacteria and test their potential to slow or stop Parkinson's progression by altering the gut ecosystem.

"These studies would be done in animals initially," he said.

"Once we know that it's safe and it's effective the next phase of this work will take that towards clinical trials."

The research team includes scientists from QUT's School of Biomedical Sciences and neurologists from the Royal Brisbane and Women's and Princess Alexandra hospitals.

They will partner with researchers at the University of Georgia in the US.

An estimated 200,000 Australians have Parkinson's disease.

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Long-Term Dementia Risk in Parkinson Disease

Affiliation.

• 1 From the Departments of Neurology (J.G., A.S.C.-P., N.D., J.M., A.D.S., A.W.W., D.W.) and Psychiatry (E.M., D.W.), and Biostatistics and Epidemiology (S.X.X.), University of Pennsylvania, Philadelphia; Department of Biostatistics (C.G., C.C.-G., C.S.C.), University of Iowa; Department of Psychiatry (R.D.D.), Rutgers University, Newark, NJ; Department of Old Age Psychiatry (D.A.), Kings College London, UK; Neurological Institute (R.N.A.), Tel Aviv Sourasky Medical Center, Israel; Department of Neurology (R.N.A.), Columbia University Irving Medical Center, New York, NY; Department of Neurology (M.J.B.), Virginia Commonwealth University, Richmond, VA; Department of Neurology (L.C.), University of Pittsburgh, PA; The Michael J. Fox Foundation for Parkinson's Research (J.L.E.), New York, NY; James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders (A.J.E.), Department of Neurology, University of Cincinnati; Cleveland Clinic (J.B.L.), Neurological Institute, Lou Ruvo Center for Brain Health, OH; Department of Neuroscience (I.L.), University of California San Diego; Parkinson's Disease Research, Education and Clinical Center (PADRECC) (J.M., D.W.), Crescenz Veteran's Affairs Medical Center, Philadelphia, PA; Department of Neurology (I.H.R.), University of Rochester, NY; Department of Neurology (L.R.), Johns Hopkins University, Baltimore, MD; and Department of Neurology (T.S.), Northwestern University, Chicago, IL; Departments of Neurology and Psychiatry and Behavioral Sciences (M.K.Y.), Baylor College of Medicine, Houston, TX.
• PMID: 39110916
• PMCID: PMC11318527
• DOI: 10.1212/WNL.0000000000209699

Background and objectives: It is widely cited that dementia occurs in up to 80% of patients with Parkinson disease (PD), but studies reporting such high rates were published over two decades ago, had relatively small samples, and had other limitations. We aimed to determine long-term dementia risk in PD using data from two large, ongoing, prospective, observational studies.

Methods: Participants from the Parkinson's Progression Markers Initiative (PPMI), a multisite international study, and a long-standing PD research cohort at the University of Pennsylvania (Penn), a single site study at a tertiary movement disorders center, were recruited. PPMI enrolled de novo, untreated PD participants and Penn a convenience cohort from a large clinical center. For PPMI, a cognitive battery is administered annually, and a site investigator makes a cognitive diagnosis. At Penn, a comprehensive cognitive battery is administered either annually or biennially, and a cognitive diagnosis is made by expert consensus. Interval-censored survival curves were fit for time from PD diagnosis to stable dementia diagnosis for each cohort, using cognitive diagnosis of dementia as the primary end point and Montreal Cognitive Assessment (MoCA) score <21 and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I cognition score ≥3 as secondary end points for PPMI. In addition, estimated dementia probability by PD disease duration was tabulated for each study and end point.

Results: For the PPMI cohort, 417 participants with PD (mean age 61.6 years, 65% male) were followed, with an estimated probability of dementia at year 10 disease duration of 9% (site investigator diagnosis), 15% (MoCA), or 12% (MDS-UPDRS Part I cognition). For the Penn cohort, 389 participants with PD (mean age 69.3 years, 67% male) were followed, with 184 participants (47% of cohort) eventually diagnosed with dementia. The interval-censored curve for the Penn cohort had a median time to dementia of 15 years (95% CI 13-15); the estimated probability of dementia was 27% at 10 years of disease duration, 50% at 15 years, and 74% at 20 years.

Discussion: Results from two large, prospective studies suggest that dementia in PD occurs less frequently, or later in the disease course, than previous research studies have reported.

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Conflict of interest statement

C. Gochanour, C. Caspell-Garcia, R.D. Dobkin, L.M. Chahine, C.S. Coffey, A.D. Siderowf, T. Simuni, M.K. York, and D. Weintraub receive financial support for their administrative roles on the PPMI study. R.D. Dobkin receives grant support from the Michael J. Fox Foundation and the VA Office of Rural Health. D. Aarsland has received research support and/or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals, Evonik, Roche Diagnostics, GE Health, and Sanofi, and has received consulting fees from H. Lundbeck, Eisai, Heptares, Mentis Cura, Eli Lilly, Cognetivity, Enterin, Acadia, EIP Pharma, Biogen, and Takeda. R.N. Alcalay has received consultation fees from Capsida, Takeda, Sanofi, Biohaven and Gain Therapeutics (paid to institution), and has received research support from the Parkinson's Foundation, the Michael J. Fox Foundation, and the Silverstein Foundation. M.J. Barrett receives research funding from the NIH (R21AG077469, R21AG074368) and Kyowa Kirin Inc., and serves as site PI for clinical trials and studies sponsored by Biogen, the CHDI Foundation, Cognition Therapeutics, EIP Pharma, uniQure, the Parkinson's Foundation, and Prilenia Therapeutics. L.M. Chahine receives research support from the Michael J. Fox Foundation, the UPMC Competitive Medical Research Fund, NIH, and the University of Pittsburgh, is site investigator for a study sponsored by Biogen, has received consulting fees from the Michael J. Fox Foundation, and receives royalties from Elsevier and Wolters Kluwer (for authorship). A. Chen-Plotkin receives research support from the NIH and the Parker Family Chair, is the inventor of a patent held by the University of Pennsylvania pertaining to genetic approaches to treating frontotemporal dementia (receives royalties for licensing). C.S. Coffey receives grant funding from the Michael J. Fox Foundation and the National Institute for Neurological Disorders and Stroke. N. Dahodwala receives grant support from the NIH (R01NS125294, U19AG062418), the Michael J. Fox Foundation, the Parkinson's Foundation, and Genentech (clinical trial), has received honoraria from Mediflix, has received consulting fees from Genentech, and has received compensation for review of medical records for Post & Schell (law firm). A.J. Espay has received grant support from the NIH and the Michael J. Fox Foundation, has received personal compensation as a consultant/scientific advisory board member for Neuroderm, Amneal, Acadia, Avion Pharmaceuticals, Acorda, Kyowa Kirin, Supernus (formerly, USWorldMeds), and Herantis Pharma, has received speaker honoraria from Avion, Amneal, and Supernus, has received publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer, is a cofounder of REGAIN Therapeutics, and is co-inventor of the patent “Compositions and methods for treatment and/or prophylaxis of proteinopathies.” J.B. Leverenz has received research support from the NIH (P30AG072959, U01NS100610, U01AG073323), GE Healthcare, the Alzheimer's Association, and the Lewy Body Dementia Association. I. Litvan has received research support from the NIH (grants: 2R01AG038791-06A, U01NS100610, R25NS098999, U19 AG063911-1, and 1R21NS114764-01A1), the Michael J. Fox Foundation, the Parkinson's Foundation, the Lewy Body Association, CurePSP, Roche, Abbvie, Biogen, Centogene, EIP-Pharma, Biohaven Pharmaceuticals, Novartis, and United Biopharma SRL UCB, is a member of the scientific advisory board for Amydis (no compensation received) and the Rossy PSP Program at the University of Toronto, and receives salary from the University of California San Diego and as Chief Editor of Frontiers in Neurology . J.F. Morley has received research funding from the NIH, the Michael J. Fox Foundation, the Department of Defense, and the Department of Veteran Affairs. I. Richard has received research and/or training grants from NIH, the Parkinson's Foundation, and the Michael J. Fox Foundation, and has served as a site investigator and/or coinvestigator for clinical research studies sponsored by industry grants to the University of Rochester, currently including F. Hoffman-La Roche Ltd., Acadia Pharm, and Jazz Pharmaceuticals. L. Rosenthal receives research support from the National Institute of Neurological Disorders and Stroke, the Daniel B. and Florence E. Green Family Foundation, and the Macks Family Foundation, and receives additional programmatic support from the Gordon and Marilyn Macklin Foundation, receives salary support from Biohaven Pharmaceuticals and Pfizer and for serving on the Clinical Events Committee for a research study with Functional Neuromodulation, and serves on the steering committees for the Parkinson Study Group's research study with both UCB and Bial Pharmaceuticals, has received personal honoraria for serving on an advisory board for Reata pharmaceuticals and Biohaven Pharmaceuticals. A.D. Siderowf has received consulting fees from Wave Life Sciences, Inhibikase, Prevail, Merck, Bial Biotech, and Takeda, has served on DSMBs for the Huntington Study Group and the Healey ALS Consortium (Massachusetts General Hospital), and has received grant funding from the Michael J. Fox Foundation, NIA, and the National Institute of Neurological Disorders and Stroke. T. Simuni has served as a consultant for AcureX, Adamas, AskBio, Amneal, Blue Rock Therapeutics, Critical Path for Parkinson's Consortium (CPP), Denali, the Michael J. Fox Foundation, Neuroderm, Sanofi, Sinopia, Roche, Takeda, and Vanqua Bio, has served on scientific advisory boards for AcureX, Adamas, AskBio, Biohaven, Denali, GAIN, Neuron23, Roche, Koneksa, Neuroderm, Sanofi, and UCB, has received research funding from Amneal, Biogen, Neuroderm, Prevail, Roche, and UCB, and has served as an investigator for National Institute of Neurological Disorders and Stroke, the Michael J. Fox Foundation, and the Parkinson's Foundation. M. York has received grant support from the NIH and the Michael J. Fox Foundation, and personal compensation as a consultant/scientific advisory board member for Bluerock, the Parkinson's Foundation, and RAD-PD. A. Willis receives financial support from NIH (grant R01NS099129), the Parkinson's Foundation, Acadia Pharmaceuticals Inc., and the University of Pennsylvania. D. Weintraub has received funding from the Michael J. Fox Foundation, the Alzheimer's Therapeutic Research Initiative (ATRI), the Alzheimer's Disease Cooperative Study (ACds0), the International Parkinson and Movement Disorder Society (IPMDS), NIH, the Parkinson's Foundation, the US Department of Veterans Affairs, and Acadia Pharmaceuticals, has received consulting fees from Acadia Pharmaceuticals, Alkahest, Aptinyx, Cerevel Therapeutics, the CHDI Foundation, Clintrex LLC (Otsuka), EcoRI Capital, Eisai, Perring, Gray Matter Technologies, Great Lake Neurotechnologies, Intra-Cellular Therapies, Janssen, Merck, Sage, Scion, and Signant Health, and receives license fee payments from the University of Pennsylvania for the QUIP and QUIP-RS. The other authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.

Figure 1. Time From PD Diagnosis to…

Figure 1. Time From PD Diagnosis to Site Investigator Dementia Diagnosis in PPMI and Penn…

Figure 2. Estimated Times From PD Diagnosis…

Figure 2. Estimated Times From PD Diagnosis to Dementia Diagnosis

Estimated times (A) by age…

Figure 3. Time From Study Enrollment to…

Figure 3. Time From Study Enrollment to Dementia Diagnosis for Participants With PD and HCs…

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Newly discovered trigger of Parkinson’s upends common beliefs

Damage starts much earlier than the death of dopamine neurons, scientists report

Media Information

• Release Date: September 15, 2023

CHICAGO --- A new Northwestern Medicine study challenges a common belief in what triggers Parkinson’s disease.

Degeneration of dopaminergic neurons is widely accepted as the first event that leads to Parkinson’s. But the new study suggests that a dysfunction in the neuron’s synapses — the tiny gap across which a neuron can send an impulse to another neuron — leads to deficits in dopamine and precedes the neurodegeneration.

Parkinson’s disease affects 1% to 2% of the population and is characterized by resting tremor, rigidity and bradykinesia (slowness of movement). These motor symptoms are due to the progressive loss of dopaminergic neurons in the midbrain.

The findings, which will be published Sept. 15 in Neuron, open a new avenue for therapies, the scientists said.

“We showed that dopaminergic synapses become dysfunctional before neuronal death occurs,” said lead author Dr. Dimitri Krainc, chair of neurology at Northwestern University Feinberg School of Medicine and director of the Simpson Querrey Center for Neurogenetics. “Based on these findings, we hypothesize that targeting dysfunctional synapses before the neurons are degenerated may represent a better therapeutic strategy.”

The study investigated patient-derived midbrain neurons, which is critical because mouse and human dopamine neurons have a different physiology and findings in the mouse neurons are not translatable to humans, as highlighted in Krainc's research recently published in Science .

Northwestern scientists found that dopaminergic synapses are not functioning correctly in various genetic forms of Parkinson’s disease. This work, together with other recent studies by Krainc’s lab, addresses one of the major gaps in the field: how different genes linked to Parkinson’s lead to degeneration of human dopaminergic neurons.

Neuronal recycling plant

Imagine two workers in a neuronal recycling plant. It’s their job to recycle mitochondria, the energy producers of the cell, that are too old or overworked. If the dysfunctional mitochondria remain in the cell, they can cause cellular dysfunction. The process of recycling or removing these old mitochondria is called mitophagy. The two workers in this recycling process are the genes Parkin and PINK1. In a normal situation, PINK1 activates Parkin to move the old mitochondria into the path to be recycled or disposed of.

It has been well-established that people who carry mutations in both copies of either PINK1 or Parkin develop Parkinson’s disease because of ineffective mitophagy.

The story of two sisters whose disease helped advance Parkinson’s research

Two sisters had the misfortune of being born without the PINK1 gene, because their parents were each missing a copy of the critical gene. This put the sisters at high risk for Parkinson’s disease, but one sister was diagnosed at age 16, while the other was not diagnosed until she was 48.

The reason for the disparity led to an important new discovery by Krainc and his group. The sister who was diagnosed at 16 also had partial loss of Parkin, which, by itself, should not cause Parkinson’s.  

“There must be a complete loss of Parkin to cause Parkinson’s disease. So, why did the sister with only a partial loss of Parkin get the disease more than 30 years earlier?” Krainc asked.

As a result, the scientists realized that Parkin has another important job that had previously been unknown. The gene also functions in a different pathway in the synaptic terminal — unrelated to its recycling work— where it controls dopamine release. With this new understanding of what went wrong for the sister, Northwestern scientists saw a new opportunity to boost Parkin and the potential to prevent the degeneration of dopamine neurons.

“We discovered a new mechanism to activate Parkin in patient neurons,” Krainc said. “Now, we need to develop drugs that stimulate this pathway, correct synaptic dysfunction and hopefully prevent neuronal degeneration in Parkinson’s.”

The first author of the study is Pingping Song, research assistant professor in Krainc’s lab. Other authors are Wesley Peng, Zhong Xie, Daniel Ysselstein, Talia Krainc, Yvette Wong, Niccolò Mencacci, Jeffrey Savas, and D. James Surmeier from Northwestern and Kalle Gehring from McGill University.

The title of the article is “Parkinson’s disease linked parkin mutation disrupts recycling of synaptic vesicles in human dopaminergic neurons.”

This work was supported by National Institutes of Health grants R01NS076054, R3710 NS096241, R35 NS122257 and NS121174, all from the National Institute of Neurological Disorders and Stroke.  

Scientists Have Discovered a New Cause of Parkinson’s Disease

A major discovery sheds light on the underlying mechanisms of Parkinson’s disease, opening the door for novel therapeutic approaches down the line.

Until recently, our understanding of Parkinson’s disease has been quite limited, manifesting in the restricted treatment options and management strategies for this debilitating condition.

Our knowledge has mostly focused on the genetic factors associated with familial cases, with the causative factors in the majority of patients remaining elusive.

However, in a new study, researchers from the University of Copenhagen have unveiled new insights into the workings of the brain in Parkinson’s patients. Leading the groundbreaking discovery is Professor Shohreh Issazadeh-Navikas.

“For the first time, we can show that mitochondria, the vital energy producers within brain cells, particularly neurons, undergo damage, leading to disruptions in mitochondrial DNA . This initiates and spreads the disease like a wildfire through the brain,” says Shohreh Issazadeh-Navikas and adds:

“Our findings establish that the spread of the damaged genetic material, the mitochondrial DNA, causes the symptoms reminiscent of Parkinson’s disease and its progression to dementia.”

Parkinson’s disease is a chronic condition that affects the central nervous system, leading to symptoms such as difficulty walking, tremors, cognitive challenges, and, eventually, dementia.

The disease afflicts over 10 million people worldwide. While there is currently no cure, certain medical treatments can offer relief from its symptoms.

Small fragments of mitochondrial DNA spreads the disease

By examining both human and mouse brains, researchers discovered that the damage to mitochondria in brain cells occurs and spreads when these cells have defects in anti-viral response genes. They sought to understand why this damage occurred and how it contributed to the disease.

Their search led to a remarkable revelation.

“Small fragments of – actually DNA – from the mitochondria are released into the cell. When these fragments of damaged DNA are misplaced, they become toxic to the cell, prompting nerve cells to expel this toxic mitochondrial DNA,” Shohreh Issazadeh-Navikas explains.  

“Given the interconnected nature of brain cells, these toxic DNA fragments spread to neighboring and distant cells, similar to an uncontrolled forest fire sparked by a casual bonfire” she adds.

The dream is a blood sample

Shohreh Issazadeh-Navikas envisions that this study marks the initial stride towards a better understanding of the disease, and the development of future treatments, diagnostics, and measurement of treatment efficacy for Parkinson’s disease.

She also expressed hope that “detecting the damaged mitochondrial DNA could serve as an early biomarker for disease development”.

Biomarkers are objective indicators of specific medical conditions observed in patients. While some biomarkers are common, such as blood pressure, body temperature and body mass index, others provide insights into particular diseases, like gene mutations in cancer or level of blood sugar for diabetes. Identifying a biomarker for Parkinson’s disease holds significant promise for enhancing future treatments.   

“It could be possible that the damage of the mitochondrial DNA in the brain cells leaks from the brain into the blood. That would make it possible to take a small sample of a patient’s blood as a way of diagnosing early on or to establish the favorable response to future treatments.”

Professor Issazadeh-Navikas also envisions the possibility of detection of damaged mitochondrial DNA in the bloodstream, making it feasible to diagnose the disease or gauge treatment responses through a simple blood test.

The researchers’ next endeavor involves investigating how mitochondrial DNA damage can serve as predictive markers for different disease stages and progression. “Furthermore, we are dedicated to exploring potential therapeutic strategies aimed at restoring normal mitochondrial function to rectify the mitochondrial dysfunctions implicated in the disease.”

Reference: “Mitochondrial DNA damage triggers spread of Parkinson’s disease-like pathology” by Emilie Tresse, Joana Marturia-Navarro, Wei Qi Guinevere Sew, Marina Cisquella-Serra, Elham Jaberi, Lluis Riera-Ponsati, Natasha Fauerby, Erling Hu, Oliver Kretz, Susana Aznar and Shohreh Issazadeh-Navikas, 2 October 2023,  Molecular Psychiatry . DOI: 10.1038/s41380-023-02251-4

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Well, 60 minutes did a story about if Washington was made king of the United States, if the family linage were followed, who would be king today. Well they traced it down to Don Washington a truck driver. Mr Washington didn’t even know he was a direct descendant of George. Don Washington was around 6 feet tall, and had dark hair, and large dark mustach. Didn’t look like George at all, but there were 12 generations out from George.

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Non-pharmacological interventions may play greater role in treatment of patients with Parkinson's disease

by IOS Press

The field of non-pharmacological interventions for the treatment of individuals with Parkinson's disease (PD) is reaching maturity and has the potential to substantially improve patient care in the future.

A supplement to the Journal of Parkinson's Disease ( JPD ) captures a wealth of information on non-pharmacological interventions addressing physical and mental perspectives as well as views on access to care.

The voices of people with Parkinson's are being heard more and more, fueling a more holistic approach to the treatment of this neurodegenerative disease.

"We are increasingly witnessing participatory research approaches in which patients are involved in designing novel treatment programs, preparing consensus statements on the delivery of multidisciplinary care, and in defining outcome measures," says co-Guest Editor of the supplement Elke Kalbe, Ph.D.

Kalbe is associated with the Medical Psychology | Neuropsychology and Gender Studies & Center for Neuropsychological Diagnostics and Intervention (CeNDI), University Hospital Cologne, and Medical Faculty of the University of Cologne, Cologne, Germany.

"Coupled with the empirical observations of clinicians who continually face the limitations of pharmacotherapy and the growing support of evidence that comes from adequately designed research studies, these developments yield a much wider perspective on patient care than previously endorsed," adds co-guest editor Bastiaan R. Bloem, MD.

Bloem is from the Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Department of Neurology, Center of Expertise for Parkinson and Movement Disorders, Nijmegen, Netherlands, and co-Editor-in-Chief of JPD .

Non-pharmacological interventions for people with PD have traditionally been regarded as supportive measures to primarily alleviate motor symptoms. While physiotherapy, speech-language therapy, and occupational therapy have gradually become integral parts of the overall management of PD, other non-pharmacological interventions like cognitive training, cognitive behavioral therapy , and art or light therapy are only just beginning to be included in therapy guidelines.

Developments that are highlighted in this supplement include:

• Expansion of the types of interventions
• Standardization of intervention protocols
• Development of digital forms of interventions
• Scientific evaluation of the feasibility and effects of the interventions
• Understanding of underlying mechanisms of therapy-induced plasticity processes
• Integration of non-pharmacological interventions in patient care concepts
• Transition from merely symptomatic to preventive therapies

The field is shifting from tackling motor to non-motor symptoms such as stress. The article "Alleviating Stress in Parkinson's Disease: Symptomatic Treatment, Disease Modification, or Both?" reviews the evidence on stress-alleviating strategies such as exercise and mindfulness-based interventions in PD, focusing both on symptomatic effects and disease-modifying effects.

The article sheds light on the impact of stress and stress-alleviation on clinical symptoms and the pathophysiology in PD.

"In people with PD, stress is thought to play a particularly important role. Not only does acute stress aggravate the symptomatic manifestations of the disease, such as tremor, dyskinesia, or freezing of gait, recent evidence in animals also suggests that chronic stress may influence the degree of nigro-striatal cell loss," says lead author Rick C. Helmich, MD, Ph.D., Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Neurology Department, Center of Expertise for Parkinson and Movement Disorders, Nijmegen, the Netherlands.

The review article "Pain and the Non-Pharmacological Management of Pain in People with Parkinson's Disease" describes pain and the biopsychosocial model of pain. It explores how pain is classified in PD and describes the three main types of pain: nociceptive, neuropathic, and nociplastic pain.

Lead author Natalie Elizabeth Allen, Ph.D., Discipline of Physiotherapy, Faculty of Medicine and Health, The University of Sydney, Australia, notes, "This background provides context for a discussion of non-pharmacological pain management strategies that may aid in the management of pain in people with Parkinson's disease including exercise, psychological strategies, acupuncture and massage.

"While there is little PD-specific research to inform the non-pharmacological management of pain, findings from current PD research are combined with that from chronic pain research to present recommendations for clinical practice. Recommendations include assessment that incorporates potential biopsychosocial contributors to pain that will then guide a holistic, multi-modal approach to management."

Other articles in the supplement highlight issues around the implementation and provision of adequate access to multidisciplinary care, the optimization of digital health literacy to enable benefits of technological approaches, innovative and valid outcome measures to capture subtle changes in symptoms and well-being, and arts-based interventions as emerging therapeutic modalities that may uniquely tackle aspects of the disease that conventional treatments cannot address.

Co-Guest Editor Lorraine V. Kalia, MD, Ph.D., Krembil Research Institute, Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, Toronto, Canada, and co-Editor-in-Chief of JPD , says, "We see that clinicians are no longer limiting their focus to traditional non-pharmacological approaches for only motor symptoms.

"For example, they are embracing preventive interventions, such as exercise, as well as arts-based interventions, such as dance and visual arts, which have the potential to offer a holistic approach to manage various motor and non-motor symptoms of PD while also enhancing overall well-being.

"In addition, novel approaches to impact cognitive impairment and affective disorders are emerging, with technology playing an important role in the delivery and outreach of non-pharmacological interventions."

Co-guest editor Alice Nieuwboer, Ph.D., KU Leuven, Department of Rehabilitation Sciences, Research Group for Neurorehabilitation (eNRGy), Leuven, Belgium, says "The scope of non-pharmacological interventions is widening, and health care professionals should prioritize these areas in their practice.

"The field of non-pharmacological therapy is clearly reaching clinical and scientific maturity and has the potential to substantially improve patient care in the future."

Natalie Elizabeth Allen et al, Pain and the Non-Pharmacological Management of Pain in People with Parkinson's Disease, Journal of Parkinson's Disease (2024). DOI: 10.3233/JPD-230227

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Parkinson's disease breakthrough: Scientists publish new findings

In a new Parkinson's disease research breakthrough, scientists have developed a technique that allows them to detect a key signature of the disease in the brain and body cells of living people.

The technique is called a-synuclein seeding amplification assay, and it can detect an abnormal protein linked with Parkinson's disease in both symptomatic and non-symptomatic people. This means it has the potential to act as an early alarm system for people who might not realize they face a high risk of developing Parkinson's.

• 5 Things to Know newsletter: Sign up to start your day with the biggest stories

"(a-synuclein seeding amplification assay) enables us to move to another level in effecting new strategies for prevention of disease," said principal investigator Dr. Ken Marek in a media release issued on April 13.

Parkinson's disease is a progressive brain disorder that causes unintended or uncontrollable movements, such as shaking, stiffness, and difficulty with balance and co-ordination. It can also lead to behavioural changes, sleep problems, depression, memory loss and fatigue.

A study detailing the breakthrough was published in the medical journal The Lancet Neurology on April 12.

According to the authors, the assay can confirm the presence of abnormal alpha-synuclein, also known as Parkinson's protein, in most people with Parkison’s with an accuracy rate of 93 per cent. The test was abnormal in less than five percent of people without Parkinson’s.

Alpha-synoclein is a protein normally found in the nervous system that, like amyloid in Alzheimer's disease, can start to misfold and clump together, damaging neurons and causing Parkinson's disease to develop. That is when it's considered abnormal alpha-synuclein.

Until now, scientists have only been able to confirm the presence of abnormal alpha-synuclein clumps in deceased patients through postmortem analysis. According to the study, being able to detect this Parkinson's biomarker in live patients could allow specialists to diagnose the disease and begin interventions earlier than ever. The researchers said it could potentially have the added benefit of keeping some newly diagnosed patients from ever advancing to full-blown symptoms.

The new technique takes advantage of a characteristic of abnormal alpha-synuclein in which it causes nearby, normal alpha-synuclein to also misfold and clump. For the assay, spinal fluid samples are prepared with a fluorescent contrast agent that lights up if alpha-synuclein clumps form.

Normal alpha-synuclein is then added to the spinal fluid sample. If abnormal alpha-synuclein is present in the sample, clumps form among the newly-introduced normal alpha-synuclein and the dye lights up. If there's no alpha-synuclein in the sample, no clumps form and the dye doesn’t light up.

The biomarker breakthrough was achieved by an international coalition of scientists as part of a large clinical study funded by the Michael J. Fox Foundation called the Parkinson’s Progression Markers Initiative (PPMI).

"We've never previously been able to see in a living person whether they have this alpha-synuclein biological change happening in their body," Todd Sherer, chief mission officer at the Michael J. Fox Foundation said in a media release, adding that by helping identify people in the earliest stages of Parkinson's, "we could then study what happens at different biological stages of the disease."

The Michael J. Fox Foundation aims to find a cure for Parkinson's disease through an aggressively funded research agenda, which includes large, open data studies like the PPMI.

Fox was diagnosed with early-onset Parkinson's Disease in 1991 at 29 years old and established the foundation in 2000.

"I’m moved, humbled and blown away by this breakthrough, which is already transforming research and care, with enormous opportunity to grow from here," Fox said in a media release published on April 13.

"I’m so grateful for the support of patients, families and researchers who are in it with us as we continue to kick down doors on the path to eradicating Parkinson’s once and for all." 

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New research reveals a potent weapon against Parkinson's disease

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Neurodegenerative diseases damage and destroy neurons, ravaging both mental and physical health. Parkinson's disease, which affects over 10 million people worldwide, is no exception. The most obvious symptoms of Parkinson's disease arise after the illness damages a specific class of neuron located in the midbrain. The effect is to rob the brain of dopamine-;a key neurotransmitter produced by the affected neurons.

In new research, Jeffrey Kordower and his colleagues describe a process for converting non-neuronal cells into functioning neurons able to take up residence in the brain, send out their fibrous branches across neural tissue, form synapses, dispense dopamine and restore capacities undermined by Parkinson's destruction of dopaminergic cells.

The current proof-of-concept study reveals that one group of experimentally engineered cells performs optimally in terms of survival, growth, neural connectivity, and dopamine production, when implanted in the brains of rats. The study demonstrates that the result of such neural grafts is to effectively reverse motor symptoms due to Parkinson's disease.

Stem cell replacement therapy represents a radical new strategy for the treatment of Parkinson's and other neurodegenerative diseases. The futuristic approach will soon be put to the test in the first of its kind clinical trial, in a specific population of Parkinson's disease sufferers, bearing a mutation in the gene parkin. The trial will be conducted at various locations, including the Barrow Neurological Institute in Phoenix, with Kordower as principal investigator.

The work is supported through a grant from the Michael J. Fox Foundation.

We cannot be more excited by the opportunity to help individuals who suffer from this genetic form of Parkinson's disease, but the lessons learned from this trial will also directly impact patients who suffer from sporadic, or non-genetic forms of this disease." Jeffrey Kordower

Kordower directs the ASU-Banner Neurodegenerative Disease Research Center at Arizona State University and is the Charlene and J. Orin Edson Distinguished Director at the Biodesign Institute. The new study describes in detail the experimental preparation of stem cells suitable for implantation to reverse the effects of Parkinson's disease.

The research appears in the current issue of the npj journal Nature Regenerative Medicine.

New perspectives on Parkinson's disease

You don't have to be a neuroscientist to identify a neuron. Such cells, with their branching arbor of axons and dendrites are instantly recognizable and look like no other cell type in the body. Through their electrical impulses, they exert meticulous control over everything from heart rate to speech. Neurons are also the repository of our hopes and anxieties, the source of our individual identity.

Degeneration and loss of dopaminergic neurons causes the physical symptoms of rigidity, tremor, and postural instability, which characterize Parkinson's disease. Additional effects of Parkinson's disease can include depression, anxiety, memory deficit, hallucinations and dementia.

Due to an aging population, humanity is facing a mounting crisis of Parkinson's disease cases, with numbers expected to swell to more than 14 million globally by 2040. Current therapies, which include use of the drug L-DOPA, are only able to address some of the motor symptoms of the disease and may produce serious, often intolerable side effects after 5-10 years of use.

There is no existing treatment capable of reversing Parkinson's disease or halting its pitiless advance. Far-sighted innovations to address this pending emergency are desperately needed.

A (pluri) potent weapon against Parkinson's

Despite the intuitive appeal of simply replacing dead or damaged cells to treat neurodegenerative disease, the challenges for successfully implanting viable neurons to restore function are formidable. Many technical hurdles had to be overcome before researchers, including Kordower, could begin achieving positive results, using a class of cells known as stem cells.

The interest in stem cells as an attractive therapy for a range of diseases rapidly gained momentum after 2012, when John B. Gurdon and Shinya Yamanaka shared the Nobel Prize for their breakthrough in stem cell research. They showed that mature cells can be reprogrammed, making them "pluripotent"-;or capable of differentiating into any cell type in the body.

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These pluripotent stem cells are functionally equivalent to fetal stem cells, which flourish during embryonic development, migrating to their place of residence and developing into heart, nerve, lung, and other cell types, in one of the most remarkable transformations in nature.

Neural alchemy

Adult stem cells come in two varieties. One type can be found in fully developed tissues like bone marrow, liver, and skin. These stem cells are few in number and generally develop into the type of cells belonging to the tissue they are derived from.

The second kind of adult stem cells (and the focus of this study) are known as induced pluripotent stem cells (iPSCs). The technique for producing the iPSCs used in the study occurs in two phases. In a way, the cells are induced to time travel, initially, in a backward and then a forward direction.

First, adult blood cells are treated with specific reprogramming factors that cause them to revert to embryonic stem cells . The second phase treats these embryonic stem cells with additional factors, causing them to differentiate into the desired target cells-;dopamine-producing neurons.

"The major finding in the in the present paper is that the timing in which you give the second set of factors is critical," Kordower says. "If you treat and culture them for 17 days, and then stop their divisions and differentiate them, that works best."

Pitch perfect neurons

The study's experiments included iPSCs cultured for 24 and 37 days, but those cultured for 17 days prior to their differentiation into dopaminergic neurons were markedly superior, capable of surviving in greater numbers and sending out their branches over long distances. "That's important," Kordower says, "because they're going to have to grow long distances in the larger human brain and we now know that these cells are capable of doing that."

Rats treated with the 17-day iPSCs showed remarkable recovery from the motor symptoms of Parkinson's disease. The study further demonstrates that this effect is dose dependent. When a small number of iPSCs were grafted into the animal brain, recovery was negligible, but a large complement of cells produced more profuse neural branching, and complete reversal of Parkinson's symptoms.

The initial clinical trial will apply iPSC therapy to a group of Parkinson's patients bearing a particular genetic mutation, known as a Parkin mutation. Such patients suffer from the typical symptoms of motor dysfunction found in general or idiopathic Parkinson's, but do not suffer from cognitive decline or dementia. This cohort of patients provides an ideal testing ground for cell replacement therapy. If the treatment is effective, larger trials will follow, applying the strategy to the version of Parkinson's affecting most patients stricken with the disease.

Further, the treatment could potentially be combined with existing therapies to treat Parkinson's disease. Once the brain has been seeded with dopamine-producing replacement cells, lower doses of drugs like L-DOPA could be used, mitigating side effects, and enhancing beneficial results.

The research sets the stage for the replacement of damaged or dead neurons with fresh cells for a broad range of devastating diseases.

"Patients with Huntington's disease or multiple system atrophy or even Alzheimer's disease could be treated in this way for specific aspects of the disease process," Kordower says.

Arizona State University

Hiller, B.M., et al. (2022) Optimizing maturity and dose of iPSC-derived dopamine progenitor cell therapy for Parkinson's disease. npj Regenerative Medicine . doi.org/10.1038/s41536-022-00221-y .

Posted in: Medical Science News | Medical Research News | Medical Condition News

Tags: Aging , Alzheimer's Disease , Anxiety , B Cell , Blood , Bone , Bone Marrow , Brain , Cell , Clinical Trial , Dementia , Depression , Dopamine , Dopaminergic , Drugs , Embryonic Development , Embryonic Stem Cells , Gene , Genetic , Heart , Heart Rate , Induced Pluripotent Stem Cells , Liver , Medicine , Multiple System Atrophy , Mutation , Nerve , Neurodegenerative Disease , Neurodegenerative Diseases , Neuron , Neurons , Parkinson's Disease , Research , Skin , Speech , Stem Cells , Tremor

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