parkinson's disease new research

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Parkinson's disease articles from across Nature Portfolio

Parkinson's disease is a progressive neurodegenerative disorder, which is characterized by motor symptoms such as tremor, rigidity, slowness of movement and problems with gait. Motor symptoms are often accompanied with fatigue, depression, pain and cognitive problems.

Latest Research and Reviews

Resequencing the complete SNCA locus in Indian patients with Parkinson’s disease

• Asha Kishore
• Manu Sharma

Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson’s disease

An exploratory analysis of the 1-year clinical trial PASADENA in individuals with early-stage Parkinson’s disease suggests that prasinezumab might reduce motor signs progression to a greater extent in those with more rapidly progressing disease.

• Gennaro Pagano
• Kirsten I. Taylor

GUCY2C signaling limits dopaminergic neuron vulnerability to toxic insults

• Lara Cheslow
• Matthew Byrne
• Scott A. Waldman

Subthalamic stimulation modulates context-dependent effects of beta bursts during fine motor control

How movement speed is neurally modulated remains poorly understood. Here, the authors recorded invasive brain signals in Parkinson’s disease patients during drawing and deep brain stimulation, showing a context-dependent relationship between reductions of movement acceleration and dynamic activity of the basal ganglia.

• Manuel Bange
• Gabriel Gonzalez-Escamilla
• Sergiu Groppa

Predictors of stress resilience in Parkinson’s disease and associations with symptom progression

• Anouk van der Heide
• Lisanne J. Dommershuijsen
• Rick C. Helmich

Neural signatures of indirect pathway activity during subthalamic stimulation in Parkinson’s disease

Subthalamic deep brain stimulation produces evoked resonant neural activity (ERNA) which has been linked to therapeutic benefit. Using a multimodal approach, the authors propose that ERNA reflects activation of the basal ganglia indirect pathway network.

• Leon A. Steiner
• David Crompton
• Luka Milosevic

News and Comment

Towards a methodological uniformization of environmental risk studies in parkinson’s disease.

• Bruno Lopes Santos-Lobato

Towards the era of biological biomarkers for Parkinson disease

Since its instigation in cancer research in the 1930s, the disease-staging concept has become a crucial tool in clinical research and medical practice. Two new papers have proposed biological staging and classification systems based on α-synuclein pathology for Parkinson disease and related conditions.

• Nobutaka Hattori

Parkinson disease pathology in inflammatory bowel disease

A new study has found evidence of α-synuclein aggregates — a key pathological hallmark of Parkinson disease — in the gut and brain in people and animals with inflammatory bowel disease.

• Heather Wood

Tackling vascular risk factors as a possible disease modifying intervention in Parkinson’s disease

• Anne E. Visser
• Nienke M. de Vries
• Bastiaan R. Bloem

Mapping the dysfunctome provides an avenue for targeted brain circuit therapy

Brain connections modulated by 534 deep-brain-stimulation electrodes revealed a gradient of circuits involved in dystonia, Parkinson’s disease, Tourette’s syndrome and obsessive-compulsive disorder. Together, these circuits begin to describe the human ‘dysfunctome’, a library of dysfunctional circuits that lead to various brain disorders.

Reply to: Questioning the cycad theory of Kii ALS–PDC causation

• Katerina Menšíková
• Raymond Rosales
• Petr Kaňovský

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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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Newly discovered genetic variant that causes Parkinson’s disease clarifies why the condition develops and how to halt it

Professor of Neurology, University of Florida

Disclosure statement

Matthew Farrer has US patents associated with LRRK2 mutations and associated mouse models (8409809 and 8455243), and methods of treating neurodegenerative disease (20110092565). He has previously received support from Mayo Foundation, GlaxoSmithKline, and NIH (NINDS P50 NS40256; NINDS R21 NS064885; 2005–2009), the Canada Excellence Research Chairs program (CIHR/IRSC 275675, 2010–17), the Weston Foundation and the Michael J Fox Foundation. His work has also been supported by the Dr. Don Rix BC Leadership Chair in Genetic Medicine (2011–2019) and most recently, by the Lee and Lauren Fixel Chair (2019-2024).

University of Florida provides funding as a founding partner of The Conversation US.

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Parkinson’s disease is a neurodegenerative movement disorder that progresses relentlessly . It gradually impairs a person’s ability to function until they ultimately become immobile and often develop dementia. In the U.S. alone, over a million people are afflicted with Parkinson’s, and new cases and overall numbers are steadily increasing.

There is currently no treatment to slow or halt Parkinson’s disease. Available drugs don’t slow disease progression and can treat only certain symptoms. Medications that work early in the disease, however, such as Levodopa , generally become ineffective over the years, necessitating increased doses that can lead to disabling side effects. Without understanding the fundamental molecular cause of Parkinson’s, it’s improbable that researchers will be able to develop a medication to stop the disease from steadily worsening in patients.

Many factors may contribute to the development of Parkinson’s, both environmental and genetic. Until recently, underlying genetic causes of the disease were unknown. Most cases of Parkinson’s aren’t inherited but sporadic, and early studies suggested a genetic basis was improbable.

Nevertheless, everything in biology has a genetic foundation. As a geneticist and molecular neuroscientist , I have devoted my career to predicting and preventing Parkinson’s disease. In our newly published research, my team and I discovered a new genetic variant linked to Parkinson’s that sheds light on the evolutionary origin of multiple forms of familial parkinsonism, opening doors to better understand and treat the disease.

Genetic linkages and associations

In the mid-1990s , researchers started looking into whether genetic differences between people with or without Parkinson’s might identify specific genes or genetic variants that cause the disease. In general, I and other geneticists use two approaches to map the genetic blueprint of Parkinson’s: linkage analysis and association studies.

Linkage analysis focuses on rare families where parkinsonism , or neurological conditions with similar symptoms to Parkinson’s, is passed down. This technique looks for cases where a disease-causing version of the gene and Parkinson’s appear to be passed down in the same person. It requires information on your family tree, clinical data and DNA samples. Relatively few families, such as those with more than two living, affected relatives willing to participate, are needed to expedite new genetic discoveries.

“Linkage” between a pathogenic genetic variant and disease development is so significant that it can inform a diagnosis. It has also become the basis of many lab models used to study the consequences of gene dysfunction and how to fix it. Linkage studies, like the one my team and I published , have identified pathogenic mutations in over 20 genes. Notably, many patients in families with parkinsonism have symptoms that are indistinguishable from typical, late-onset Parkinson’s. Nevertheless, what causes inherited parkinsonism, which typically affects people with earlier-onset disease, may not be the cause of Parkinson’s in the general population.

Conversely, genome-wide association studies, or GWAS , compare genetic data from patients with Parkinson’s with unrelated people of the same age, gender and ethnicity who don’t have the disease. Typically, this involves assessing how frequently in both groups over 2 million common gene variants appear. Because these studies require analyzing so many gene variants, researchers need to gather clinical data and DNA samples from over 100,000 people.

Although costly and time-consuming, the findings of genome-wide association studies are widely applicable. Combining the data of these studies has identified many locations in the genome that contribute to the risk of developing Parkinson’s. Currently, there are over 92 locations in the genome that contain about 350 genes potentially involved in the disease. However, GWAS locations can be considered only in aggregate ; individual results are not helpful in diagnosis nor in disease modeling, as the contribution of these individual genes to disease risk is so minimal.

Together, “linked” and “associated” discoveries imply a number of molecular pathways are involved in Parkinson’s. Each identified gene and the proteins they encode typically can have more than one effect. The functions of each gene and protein may also vary by cell type. The question is which gene variants, functions and pathways are most relevant to Parkinson’s? How do researchers meaningfully connect this data?

Parkinson’s disease genes

Using linkage analysis, my team and I identified a new genetic mutation for Parkinson’s disease called RAB32 Ser71Arg . This mutation was linked to parkinsonism in three families and found in 13 other people in several countries, including Canada, France, Germany, Italy, Poland, Turkey, Tunisia, the U.S. and the U.K.

Although the affected individuals and families originate from many parts of the world, they share an identical fragment of chromosome 6 that contains RAB32 Ser71Arg. This suggests these patients are all related to the same person ; ancestrally, they are distant cousins. It also suggests there are many more cousins to identify.

With further analysis, we found RAB32 Ser71Arg interacts with several proteins previously linked to early- and late-onset parkinsonism as well as nonfamilial Parkinson’s disease . The RAB32 Ser71Arg variant also causes similar dysfunction within cells .

Together, the proteins encoded by these linked genes optimize levels of the neurotransmitter dopamine . Dopamine is lost in Parkinson’s as the cells that produce it progressively die. Together, these linked genes and the proteins they encode regulate specialized autophagy processes . In addition, these encoded proteins enable immunity within cells .

Such linked genes support the idea that these causes of inherited parkinsonism evolved to improve survival in early life because they enhance immune response to pathogens. RAB32 Ser71Arg suggest how and why many mutations have originated, despite creating a susceptible genetic background for Parkinson’s in later life.

RAB32 Ser71Arg is the first linked gene researchers have identified that directly connects the dots between prior linked discoveries. The proteins encoded bring together three important functions of the cell: autophagy, immunity and mitochondrial function . While autophagy releases energy stored in the cell’s trash, this needs to be coordinated with another specialized component within the cell, mitochondria, that are the major supplier of energy. Mitochondria also help to control cell immunity because they evolved from bacteria the cell’s immune system recognizes as “self” rather than as an invading pathogen to destroy.

Identifying subtle genetic differences

Finding the molecular blueprint for familial Parkinson’s is the first step to fixing the faulty mechanisms behind the disease. Like the owner’s manual to your car’s engine, it provides a practical guide of what to check when the motor fails.

Just as each make of motor is subtly different, what makes each person genetically susceptible to nonfamilial Parkinson’s disease is also subtly different. However, analyzing genetic data can now test for types of dysfunction in the cell that are hallmarks of Parkinson’s disease. This will help researchers identify environmental factors that influence the risk of developing Parkinson’s, as well as medications that may help protect against the disease.

More patients and families participating in genetic research are needed to find additional components of the engine behind Parkinson’s. Each person’s genome has about 27 million variants of the 6 billion building blocks that make up their genes. There are many more genetic components for Parkinson’s that have yet to be found.

As our discovery illustrates, each new gene that researchers identify can profoundly improve our ability to predict and prevent Parkinson’s.

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• Genetic disease
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• Genome-wide association studies (GWAS)
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IRP Scientists Win Breakthrough Prize for Parkinson’s Discoveries

Andrew Singleton and Ellen Sidransky Lauded for Genetics Research

By Melissa Glim

Monday, November 13, 2023

Dr. Ellen Sidransky (left) and Dr. Andrew Singleton (right) received the 2024 Breakthrough Prize for discovering two of the most common genetic contributors to Parkinson’s disease.

Throughout history, some of the most important insights about devastating illnesses have come from identifying genes that contribute to them. Parkinson’s disease, a neurological condition that robs patients of the ability to move, is just one example of this pattern — and one that IRP researchers have made critical advances on in recent years.

Reflecting the IRP’s groundbreaking research on Parkinson’s disease, in September, IRP senior investigators Ellen Sidransky, M.D. , and Andrew Singleton, Ph.D. , were awarded the prestigious Breakthrough Prize for their research on the genetic causes of the illness. The world’s largest scientific award, the Breakthrough Prize honors “transformative advances toward understanding living systems and extending human life.” Each year, one award in the Life Sciences category is reserved for research on Parkinson’s and other neurodegenerative disorders. Dr. Sidransky and Dr. Singleton, along with a third Parkinson’s researcher, Thomas Gasser, M.D., Ph.D., at the University of Tübingen in Germany, will share the $3 million prize.

Dr. Singleton and Dr. Sidransky each discovered a genetic cause of the neurological disease, which affects more than 500,000 Americans. We spoke with them to learn more about their discoveries.

One Mutation, Two Diseases

Dr. Ellen Sidransky never set out to find a gene for Parkinson’s disease. As a pediatrician and researcher at NIH’s National Human Genome Research Institute (NHGRI) , she was interested in Gaucher disease, a rare genetic disorder that causes cellular garbage to pile up instead of getting recycled or thrown out. However, as her research in Gaucher disease advanced, people with Parkinson’s disease, or family histories of it, kept showing up among her patients. She began to suspect there was a connection.

Gaucher disease is a rare, inherited disorder caused by two faulty copies of a gene called GBA1 . People with the disease lack the enzyme needed to break down fat molecules called lipids, causing them to build up in organs like the liver and spleen. The illness can also affect the brain, eyes, lungs, and bones.

Enlarged cells stuffed with lipids in the spleen of a person with Gaucher disease.

Of the many patients with Gaucher disease Dr. Sidransky treated at the NIH Clinical Center, one woman in her 40s stood out. She had also developed early-onset Parkinson’s disease and donated her body to NIH upon her death. Dr. Sidransky began asking colleagues if they ever saw patients with both diseases. The answer from many was “yes.”

“Every clinic seemed to have a few cases, so I set up some collaborations and collected DNA from about 20 patients,” Dr. Sidransky says. After publishing a series of case studies about these patients, a doctor in Boston found her paper and offered to send her tissue samples from a patient with both Gaucher and Parkinson’s, along with tissue from other Parkinson’s patients for comparison.

“When the three sample sets arrived, the labels were blurred, so I said, ‘Let’s sequence the gene in all three and see if we can identify the one with Gaucher,’” Dr. Sidransky recalls. When the results came back, the patient with Gaucher disease had two mutated copies of the GBA1 gene. The surprise, Dr. Sidransky says, was that the other two samples — from people with Parkinson’s disease but not Gaucher disease — showed the individuals still had one mutated copy of the gene, meaning they could pass the genetic change on to their children without exhibiting symptoms of Gaucher disease themselves.

“This really blew us away,” Dr. Sidransky says. “I immediately reached out to all kinds of brain tissue banks for samples from patients with Parkinson’s disease. Out of 57 patients, 12 had mutations in the Gaucher gene, which was an awful lot.”

That observation spurred her to spearhead a large international collaboration that included 10,000 patients and healthy individuals. The study determined that patients with Parkinson’s disease were at least five times more likely to have a mutation in the GBA1 gene than people without Parkinson’s. 1

The link between GBA1 mutations and Parkinson’s disease risk may point to a shared treatment for at least some cases of Parkinson’s disease. In Gaucher disease, patients are treated with infusions of the missing enzyme that they need to break down fats, but this treatment cannot enter the brain. Dr. Sidransky is currently working with colleagues at the National Center for Translational Sciences (NCATS) to identify a therapy that could pump up low levels of that fat-busting enzyme in patients with Parkinson’s.

“If we come up with a treatment and assume that maybe 10 percent of patients with Parkinson’s disease have the GBA1 mutation, the drugs we develop could impact those patients,” Dr. Sidransky says. “In addition, there is evidence that even patients with run-of-the-mill Parkinson’s without this mutation also have lower than normal levels of the enzyme, so it’s theoretically possible that any drug that raises its level could help those patients as well.”

Dr. Sidransky’s laboratory has also been developing better tools for identifying appropriate drugs and building better cellular models of both Gaucher and Parkinson’s disease, including neurons grown from induced pluripotent stem cells that have GBA1 mutations. 2 Her lab is also hard at work creating better tests to measure the levels of enzyme activity in cells and patients. In addition, they have been recruiting patients for clinical trials, including pairs of siblings in which both have Gaucher disease but only one has Parkinson’s. Ultimately, Dr. Sidransky’s team hopes its research will identify other factors that may raise or lower the risk of developing Parkinson’s disease.

“We study rare diseases to help the patients with rare diseases and because they’re fascinating,” says Dr. Sidransky, “but we also study them because they can sometimes give us a really unique perspective into medicine in general.”

Treating Parkinson’s at the Genetic Roots

Dr. Andrew Singleton has been studying genetic changes that contribute to Parkinson’s disease for more than 20 years.

For Dr. Andrew Singleton, Parkinson’s disease represents an intriguing puzzle that underlies so much of biology. He is using genetic science to understand why a single disease can look so different in different patients, even those who carry the same contributing mutation. He began tackling this question at the start of his career, working in the lab of John Hardy, Ph.D., first at the Mayo Clinic in Florida and then when they came together to NIH’s National Institute on Aging (NIA) .

“I thought Parkinson’s disease was an untapped area,” Dr. Singleton recalls. “The idea of genetics is to understand disease at its most biological basis. If we can find a gene that imports risk for a disease or causes a disease, that’s a starting point for understanding the disease at the molecular level. Of course, once you understand the process, you can develop therapeutics against it.”

Working in Dr. Hardy’s lab, Dr. Singleton and his colleagues at NIH and several universities around the world began sequencing gene after gene to find the ones contributing to Parkinson’s disease. They ultimately found several genes that were involved in the illness, but one stood out as unusual: the LRRK2 gene, which codes for proteins involved in neuron development. 3 Mutations or damage to this gene raise the risk of developing Parkinson’s disease by causing it to produce an over-active form of a molecular switch called a kinase, which turns biological activity on and off. This makes it a promising target for drug therapy.

“Before this discovery, therapeutics for Parkinson’s disease really focused on treating symptoms, but that’s never going to stop the disease,” Dr. Singleton says. “Here, the idea is to understand this disease at the molecular level and then develop therapeutics that will actually stop it.”

Since Dr. Singleton and his labmates linked LRRK2 to Parkinson’s disease in 2004, mutated versions of the gene have been confirmed as the most common cause of inherited forms of Parkinson’s disease, as well as an important risk factor for other forms of the disease. Now, he is building on that work by continuing to explore the biological basis of Parkinson’s disease. This work complements, and promises to be enhanced by, related efforts within NIH’s Intramural Center for Alzheimer’s and Related Dementias (CARD), for which Dr. Singleton serves as Director. Meanwhile, Dr. Singleton is keen to see the results of an ongoing phase III clinical trial being run by pharmaceutical company Denali Therapeutics, which is testing a drug that inhibits the activity of the kinase produced by LRRK2 .

NIH’s Intramural Center for Alzheimer’s and Related Dementias resides in Building T44 on the main NIH campus in Bethesda, Maryland.

“The LRRK2 discovery has been incredibly influential,” Dr. Singleton says.

Indeed, Dr. Singleton’s work has spurred researchers around the world to study LRRK2 . When he first began to search for and sequence the gene, Dr. Singleton’s small, international team was unusual in a field full of individual gene-hunters. Today, however, work on the genetics of Parkinson’s disease is becoming much less competitive and much more collaborative.

“We're competing collectively with the disease rather than with each other,” he says.

Dr. Singleton now leads a large, international collaboration called the Global Parkinson's Genetics Program, which is collecting genetic samples from 200,000 people around the world. The researchers involved in the project hope to identify more genetic factors that might influence inherited forms of Parkinson’s disease and offer additional treatment targets.

“I think it’s particularly interesting to start to put together networks and pathways that are involved in the disease process,” Dr. Singleton says. “The same mutation and the same disease can be so different. It’s still early days in this space.”

Subscribe to our weekly newsletter  to stay up-to-date on the latest breakthroughs in the NIH Intramural Research Program.

References:

[1] Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Dürr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med . 2009 Oct 22;361(17):1651-61. doi: 10.1056/NEJMoa0901281.

[2] Aflaki E, Borger DK, Moaven N, Stubblefield BK, Rogers SA, Patnaik S, Schoenen FJ, Westbroek W, Zheng W, Sullivan P, Fujiwara H, Sidhu R, Khaliq ZM, Lopez GJ, Goldstein DS, Ory DS, Marugan J, Sidransky E.  A New Glucocerebrosidase Chaperone Reduces α-Synuclein and Glycolipid Levels in iPSC-Derived Dopaminergic Neurons from Patients with Gaucher Disease and Parkinsonism.   J Neurosci.  2016;36(28):7441-52. doi: 10.1523/JNEUROSCI.0636-16.2016.

[3] [Paisán-Ruı́z C, Jain S, Evans E, Gilks WP, Simón J, van der Brug M, López de Munain A, Aparicio S, Martinez Gil A, Khan N, Johnson J, Ruiz Martinez J, Nicholl D, Marti Carrera I, Saénz Peňa A, de Silva R, Lees A, Martí-Massó JF, Pérez-Tur J, Wood NW, Singlton AB. Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease.   Neuron . 2004; 44(4): 595-600. doi:10.1016/j.neuron.2004.10.023.

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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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Ai identifies new potential treatments for parkinson’s disease.

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AI has been used to identify potential new drugs for Parkinson's Disease.

A new artificial intelligence (AI) based strategy has significantly sped up the identification of potential new drugs to treat Parkinson's disease. The work, published in the journal Nature Chemical Biology , could mean that new treatments for Parkinson's reach clinical trials and patients more quickly.

Drug discovery for serious diseases is often a slow, laborious and expensive process. Developing a drug from early laboratory testing through to full approval for use in patients typically takes 10-15 years.

“This is an extremely time-consuming process – just identifying a lead candidate for further testing can take months or even years," said Michele Vendruscolo leader of the research and professor in the Yusuf Hamied Department of Chemistry at the University of Cambridge in the U.K.

AI and machine learning techniques have shown promise in speeding up the initial stage of this process, by discovering potential drugs for cancers and several other diseases, leading dozens of biomedical startup companies to bet on the potential of AI for drug discovery.

"One route to search for potential treatments for Parkinson’s requires the identification of small molecules that can inhibit the aggregation of alpha-synuclein, which is a protein closely associated with the disease," said Vendruscolo in a press release .

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The new study showed how an AI-based strategy sped up this process significantly and was a thousand times cheaper than traditional methods, identifying a small number of potentially useful compounds which were taken forward for laboratory testing. The results from these experiments were then fed back into the machine learning model to further optimize the predictions.

“The use of AI to develop machine learning approaches to drug discovery for protein aggregation diseases like Parkinson’s, has definitely arrived," said Michael S. Okun, M.D., National Medical Advisor for the Parkinson’s Foundation and Director of the Fixel Institute for Neurological Diseases at the University of Florida. "The over 20-fold improvement over typical high-throughput drug screening hit rates was impressive in this study and will add to the list of potential drugs to consider for clinical trials," added Okun, who was not involved in the research.

Nearly 90,000 Americans are diagnosed with Parkinson's disease annually, according to the Parkinson's Foundation, with a million people in the U.S. currently living with the disease. Despite this, there are currently no curative treatments for the disease, only drugs to manage symptoms which include tremors, balance and mobility issues and muscle stiffness.

"Machine learning is having a real impact on drug discovery – it’s speeding up the whole process of identifying the most promising candidates," said Vendruscolo. “For us, this means we can start work on multiple drug discovery programmes – instead of just one. So much is possible due to the massive reduction in both time and cost – it’s an exciting time."

However, discovering promising new compounds is only one, very early step in actually getting tried and tested drugs to patients.

“Whether this innovation however, will speed discovery of new Parkinson’s therapeutics is complicated, as introducing more compounds could actually slow the pipeline," said Okun. "Thus, a parallel and large investment will be needed in basic science research to better understand the pathogenesis of Parkinson’s disease and to more precisely apply this, and other novel AI derived drug discovery methodologies.”

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Why detecting the earliest biological signs of Parkinson’s disease is so crucial

Parkinson's disease is the second most common neurodegenerative disease, behind Alzheimer's disease, and affects nearly a million people in the United States.

The disease causes dopamine-producing brain cells to die and patients typically experience tremor, stiff muscles and slow movement as well as cognitive deficits. Medications to increase dopamine levels can help alleviate many of the motor symptoms -- but there is no cure.

Kathleen Poston , MD, the Edward F. and Irene Thiele Pimley Professor II in Neurology and the Neurological Sciences, has dedicated her career to helping patients with Parkinson's and to studying its root causes in the lab.

There were also a lot of unknowns, which piqued the interest of the research part of my brain. Kathleen Poston

Her interest in Parkinson's developed during her medical training. "As a clinician, it was a rewarding field because, compared to other neurodegenerative diseases, there were many therapies we could offer patients," she said. "But there were also a lot of unknowns, which piqued the interest of the research part of my brain."

Recently, Poston's lab has been part of an international effort supported by the Michael J. Fox Foundation for Parkinson's Research to develop a diagnostic test that can detect the earliest biological signs of the disease.

They've shown that the new biomarker -- a clumping protein in the brain -- can predict who will go on to develop Parkinson's, giving patients and researchers more time to test experimental treatments.

We asked Poston about the latest advances in the field and how early diagnosis may finally lead to a cure. This interview has been edited for clarity and brevity.

How has our understanding of Parkinson's disease changed in recent years?

The biggest shift recently has to do with our understanding of how to diagnose the disease. With certain types of brain scanning and now with a biological marker, we can be more precise and accurate in our diagnosis earlier.

Traditionally we've only been able to diagnose people with Parkinson's disease based on the same standardized exam that's been done for 50, 60 years. We rate someone's motor symptoms -- slowness, stiffness, tremor. But it's hard to identify people early on in the disease. Until somebody really had those symptoms, it was hard to say for certain, "Yes, you have Parkinson's disease." Patients often say it took two years for them to be diagnosed, or they had to see four or five different doctors.

I think it's meaningful to people living with the disease just to get the right diagnosis as early as possible. People can manage once they know what they're dealing with. But when you're in that unknown time, it's very, very hard.

The newer biomarker we can test for now is alpha-synuclein. Does everyone who has this biomarker go on to develop Parkinson's?

Alpha-synuclein is a protein we all have in our brains, but for some reason it's in these clumping forms in people who have Parkinson's disease. We now know it's the primary protein that makes up Lewy bodies, the protein aggregates that form in the brain cells that die in people with Parkinson's disease.

It wasn't until after someone died that a pathologist could look at their brain under a microscope and make a definitive diagnosis. Blood tests and brain scans didn't seem to work. Kathleen Poston

We've never been able to definitively identify, during a person's lifetime, whether they have these Lewy bodies in their brain, even if they have a clinical diagnosis of Parkinson's or a similar clinical disorder called dementia with Lewy bodies. It wasn't until after someone died that a pathologist could look at their brain under a microscope and make a definitive diagnosis. Blood tests and brain scans didn't seem to work.

We now have the first test that accurately identifies clumping alpha-synuclein. Researchers put seeds of alpha-synuclein in a sample of the patient's cerebral spinal fluid, then stress it by putting it through a series of heating, shaking and fragmenting to see if this nucleus clumps together. The test has extraordinary accuracy to the final pathology. It's about 99% accurate in people with a clinical diagnosis and also very accurate in people prior to a clinical diagnosis.

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What we don't know -- and the reason this is all still in research -- is whether a person with a positive test will develop Parkinson's disease in a year, or five years, or 10 years. It's just a "yes" or "no" readout, which doesn't tell you anything about how bad the disease is or when it will develop. So there's a lot more work that needs to be done.

You're part of a group that recently published a proposal for a biological definition of Parkinson's based on alpha-synuclein. What does that mean and why is it important?

If we're trying to come up with a therapy that can prevent someone who has the underlying biology of Parkinson's disease from ever developing clinical symptoms, we need a biological definition that's 100% based on biomarkers -- such as clumping alpha-synuclein -- and not dependent on clinical symptoms.

Right now, this biological definition is proposed strictly in research settings so we can identify people with that biology who we would want to enroll in preventative clinical trials.

The earlier we can identify people who we feel confident have Parkinson's disease, the more we can think about slowing or stopping the disease progression. It gives us a window into the disease when there's not as much damage done, when it's easier to test potential therapies.

You have an exciting paper coming up later this year. Can you tell us what that will be about?

Here at Stanford we've been banking cerebral spinal fluid samples for a long time. In the new study, we showed that the alpha-synuclein test was able to predict a future diagnosis of Parkinson's in multiple people.

Also, it turns out, about 10% to 20% of people with Alzheimer's disease at death will also have this Lewy body pathology in their brain -- and now we can detect that earlier. That could change how we think about treating people with Alzheimer's as well.

That could change how we think about treating people with Alzheimer's as well. Kathleen Poston

This is the big advantage of having the combination of banked samples, longitudinal clinical testing and individuals agreeing to autopsy and having that final diagnosis -- being able to put the whole story together. It's wonderful that all these participants volunteered to give all this information over the past 15 years and we were able to rapidly make use of it.

Looking forward, what are you most excited about?

There are two things that really excite me.

I'm working with other researchers to translate this alpha-synuclein test into a simple blood test or some other test that is readily accessible. Doing this test in the cerebral spinal fluid is quite restrictive and not every person is going to get a lumbar puncture at their annual wellness checkup.

We're doing plasma banking for all the people diagnosed with Parkinson's in our clinic. When one of my collaborators here develops something that takes it from cerebral spinal fluid into plasma, we can then quickly test it on 500 to 600 samples from our clinic.

What also excites me is figuring out how we can really accelerate therapeutic development to get to that preventive therapy. I'm working with researchers here at Stanford who are interested in therapies targeting these clumping proteins.

I hope that, in a couple of years, we're having this conversation and I'm telling you about the first FDA-approved disease-modifying therapy for Parkinson's disease. That would be wonderful.

Image courtesy Michael J. Fox Foundation for Parkinson's Research

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Early-stage trial for Parkinson’s disease therapy shows signs of promise

Small trial of Bemdaneprocel, which aims to replace dopamine-producing neurons, raises hope for treatment

Scientists have reported early success in a trial of an experimental cell therapy for Parkinson’s disease, raising hope for patients.

Bemdaneprocel therapy is at an early stage, and the year-long trial involved just 12 patients, but the positive outcome is viewed as significant after decades of setbacks in the hunt for an effective treatment. Developed by BlueRock therapeutics, a subsidiary of the pharmaceutical company Bayer, it was shown to be safe and the data gave a tantalising suggestion that patients may have benefited.

“The data from this phase 1 open label study are extremely encouraging,” said Claire Henchcliffe, a neurologist at the University of California, Irvine, who was one of the study’s principal investigators. “While this is a small open label study, meeting the study’s primary objective for safety and tolerability along with initial improvements seen in clinical outcomes represents a great step forward. The hope now is that these trends continue and translate into meaningful benefit for people with Parkinson’s disease in controlled clinical trials.”

Parkinson’s is a neurodegenerative disorder in which dopamine-producing neurons are progressively lost, causing symptoms including a tremor, slow movements and muscle stiffness. By the time people are diagnosed, they have typically already lost more than half these specialised neurons. While there are treatments that can help control symptoms, there is nothing yet that can slow or reverse the progression of the disease.

Bemdaneprocel involves an injection into the brain of dopamine-producing neurons grown from human embryonic stem cells in the lab. The hope is that these replacement cells will integrate with existing brain circuits and reverse the effects of the disease.

The study found that the treatment was safe and did not cause significant side-effects. Specialised PET imaging scans showed that the injected cells had survived and appeared to have integrated. The trial was not designed to demonstrate the efficacy of the treatment but patients showed some improvements in symptoms, with those who received the high dose showing the biggest effects.

Parkinson’s symptoms tend to fluctuate and doctors use a tool called the Hauser diary in which patients record how much of the time they are affected by motor symptoms. Patients on the high dose showed an average improvement of 2.2 hours each day without troubling symptoms compared with their baseline before treatment. Patients on the low dose showed an improvement of 0.7 hours. A change of about an hour on the scale is generally viewed as the threshold for a clinically relevant effect.

Claire Bale, an associate director of research at Parkinson’s UK, said: “It’s great news, particularly that they’re able to crack on with phase 2 so quickly, and it’s great seeing the brain scans looking like the grafts are surviving.”

However, Bale cautioned that double-blinded studies were essential to confirm efficacy, and the placebo effect was a particularly strong confounder in Parkinson’s disease trials. This is because feeling excited and hopeful (as might be the case for trial participants) can trigger the release of dopamine, the chemical that is depleted as a result of the disease. This temporary dopamine rise can lead to an apparent improvement, even as neurons are continuing to be lost. “It’s a real biological effect,” Bale said.

Seth Ettenberg, the chief executive of BlueRock therapeutics, said: “It’s a very small patient population, we’re only following up to one year after being implanted with the cells and every patient knows they’re being treated with a potentially active treatment. That said, it’s incredibly exciting.”

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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.  

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Research News

Read the latest developments, reporting and analysis from the world of Parkinson's research, including progress made in studies, tools and collaborations funded by The Michael J. Fox Foundation.

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The Parkinson's Progression Markers Initiative is changing how patients, families, doctors and scientists think about brain disease. Now it needs you.

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New research challenges conventional picture of Parkinson's disease

by Arizona State University

Parkinson's disease, the second most common type of progressive dementia after Alzheimer's disease, affects nearly 1 million people in the U.S. and an estimated 10 million individuals worldwide. Each year, close to 90,000 new cases of Parkinson's disease are diagnosed in the U.S.

In a new study, Jeffrey Kordower, director of the ASU-Banner Neurodegenerative Disease Research Center, and his colleagues unveil pivotal insights into the progression of Parkinson's disease, presenting new hope for patients battling the severely debilitating disorder.

The research highlights the role of a critical protein called tau in the early stages of the disease. The results suggest that aggregates of the tau protein may jump-start processes of neuronal damage and death characteristics of the disease.

The findings challenge the conventional view of Parkinson's disease pathology, which typically focuses on the protein alpha-synuclein as the classic diagnostic hallmark of the disease. The new study illustrates how tau pathology could be actively involved in the degeneration of dopamine-producing neurons in the brain , independent of alpha-synuclein. This revelation could shift the focus of Parkinson's disease research, diagnosis, and treatment.

"Currently, a protein called alpha-synuclein is believed to be the main player in Parkinson's disease pathogenesis," says Kordower, who is also a professor with ASU's School of Life Sciences. "This study highlights that misfolded tau may be the first player in causing the cardinal motor symptoms in the disease."

The paper is published in the journal Brain .

Shattering progression

The progression of Parkinson's disease involves distinct stages, and the timeline can vary significantly among individuals. The typical stages of Parkinson's, as outlined by the Parkinson's Foundation, can help patients understand the changes as they occur.

The disease impacts people in different ways, and not everyone will experience all the symptoms or experience them in the same order or intensity. Some may experience the changes over 20 years or more; for others, the disease advances rapidly.

The progression of the disease is influenced by a combination of genetic and environmental factors. Following a diagnosis, many individuals experience a good response to medications such as levodopa, and this optimal time frame can last for many years. Over time, however, modifications to medication are often needed, and symptoms may intensify.

The prevalence of Parkinson's has doubled in the past 25 years, which may be related to population growth, aging, genetic predisposition, lifestyle changes, and environmental pollution.

A fresh perspective

The tau protein accumulates in two regions: the substantia nigra and putamen, both part of the basal ganglia in the brain. The substantia nigra is responsible for the production of dopamine, which is critical for modulating movement, cognitive executive functions, and emotional limbic activity.

The putamen, a component of the dorsal striatum, is involved in movement initiation, selection, and decision-making, as well as learning, memory, language, and emotion. Dysfunction in the putamen can contribute to various disorders, particularly those related to motor function .

A wide range of physical and mental symptoms characterize Parkinson's disease. These include rhythmic tremors, often beginning in a limb, such as a hand or fingers; slowness of movement, which can lead to difficulty in performing simple tasks; muscle stiffness or rigidity; and difficulties with balance.

In addition to these physical symptoms, Parkinson's disease can also cause various mental and emotional changes, including depression and anxiety, sleep disorders, memory difficulties, fatigue, and emotional changes.

Brain traces of disease

The scientists conducted the study using postmortem brain tissue from older adults who had experienced different degrees of motor impairment. The research analyzed brain tissues from individuals with no motor deficits, mild motor deficits with and without Lewy pathology in the nigral region of the brain, and from individuals clinically diagnosed with Parkinson's disease.

Lewy bodies are abnormal aggregates of the protein alpha-synuclein that accumulate in the brain, and they are a hallmark of several neurodegenerative disorders, including Parkinson's and dementia with Lewy bodies.

In the case of Parkinson's, Lewy bodies are primarily found in the substantia nigra , a region of the brain that is crucial for movement control, which leads to characteristic motor symptoms such as rigidity, tremors and bradykinesia (slow movement).

The study focused on a cohort of subjects with mild motor impairments—not pronounced enough to diagnose Parkinson's, but still significant. Dividing these subjects based on the presence or absence of α-synuclein, researchers found that tau pathology was a common denominator.

The researchers observed that the brain tissue associated with minimal motor deficit demonstrated similar accumulations of tau to those with advanced Parkinson's, suggesting that tau's role occurs early in the disease's evolution. These findings open doors to earlier diagnosis and intervention, potentially slowing or altering the disease's progression.

The research also sheds light on parkinsonism, a condition that mimics Parkinson's disease symptoms but is distinct in its underlying mechanisms. The study suggests that tau pathology in the nigrostriatal region of the brain is a shared characteristic, offering a new lens through which to view and treat various forms of Parkinsonism.

The findings also underscore the potential of targeting tau pathology as a therapeutic approach to Parkinson's disease. Because tau aggregation correlates with motor deficits and degeneration of dopamine-producing regions of the brain, interventions aimed at reducing tau accumulation could offer new hope for altering the disease's trajectory.

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Newly discovered trigger for Parkinson's may lead to better treatment avenues

Parkinson's connection, personal information.

New research provides hope for Parkinson's disease symptom control

Using data from health trackers, researchers identify smarter medication regimens.

Finding the right medication regimen to treat Parkinson's disease (PD) is a complex healthcare challenge. Wearable health trackers provide physicians with a detailed window into patients' symptoms, but translating this complex data into useful treatment insights can be difficult. New research in the INFORMS journal Management Science accomplishes just that. Researchers found that combining wearable health tracker data with state-of-the-art algorithms results in promising treatment strategies that could improve PD patients' outcomes.

"Our model identified a Parkinson's disease medication strategy: Frequent dosing of a slow-release medication formulation that would benefit almost all patients," says Matt Baucum of Florida State University, one of the study authors.

"In fact, our model uses wearable sensors to predict that patients would spend almost twice as long each day (82% longer) with well-managed symptoms under our recommended medication strategy, compared with their existing medication regimens."

The paper, "Optimizing Patient-Specific Medication Regimen Policies Using Wearable Sensors in Parkinson's Disease," suggests the resulting models can offer novel clinical insights and medication strategies that can potentially democratize access to improved care.

"Our research suggests that combining rich data from wearable health trackers with the pattern-discovery capabilities of machine learning can uncover treatment strategies that otherwise might have gone underutilized," says Anahita Khojandi, study co-author from the University of Tennessee, Knoxville.

"The algorithms we developed can even be used to predict patients who might benefit from more advanced PD therapies, which really highlights their ability to extract the maximum value from wearable data."

Baucum and Khojandi, alongside fellow authors Dr. Rama Vasudevan of Oak Ridge National Laboratory and Dr. Ritesh Ramdhani a neurologist at Hofstra/ Northwell, emphasize that this work is groundbreaking for PD patients who may experience improved symptom control through continuous sensor monitoring and a novel AI approach.

"The results of this research offer the potential to revolutionize the care of PD patients by harnessing the power of AI to inform and enhance treatment decisions for a disease whose symptoms are frequently changing," says Ritesh Ramdhani.

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Materials provided by Institute for Operations Research and the Management Sciences . Note: Content may be edited for style and length.

Journal Reference :

• Matt Baucum, Anahita Khojandi, Rama Vasudevan, Ritesh Ramdhani. Optimizing Patient-Specific Medication Regimen Policies Using Wearable Sensors in Parkinson’s Disease . Management Science , 2023; DOI: 10.1287/mnsc.2023.4747

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Strange & offbeat.

New research challenges conventional picture of Parkinson's disease

A new study highlights the role of misfolded tau proteins in the genesis and trajectory of Parkinson's disease. Graphic by Jason Drees/ASU

Parkinson's disease, the second most common type of progressive dementia after Alzheimer's disease, affects nearly 1 million people in the U.S. and an estimated 10 million individuals worldwide. Each year, close to 90,000 new cases of Parkinson’s disease are diagnosed in the U.S.

In a new study, Jeffrey Kordower , director of the ASU-Banner Neurodegenerative Disease Research Center , and his colleagues unveil pivotal insights into the progression of Parkinson's disease, presenting new hope for patients battling the severely debilitating disorder.

The research highlights the role of a critical protein called tau in the early stages of the disease. The results suggest that aggregates of the tau protein may jump-start processes of neuronal damage and death characteristics of the disease.

The findings challenge the conventional view of Parkinson’s disease pathology, which typically focuses on the protein alpha-synuclein as the classic diagnostic hallmark of the disease. The new study illustrates how tau pathology could be actively involved in the degeneration of dopamine-producing neurons in the brain, independent of alpha-synuclein. This revelation could shift the focus of Parkinson’s disease research, diagnosis and treatment.

“Currently, a protein called alpha-synuclein is believed to be the main player in Parkinson’s disease pathogenesis,” says Kordower, who is also a professor with ASU’s School of Life Sciences . “This study highlights that misfolded tau may be the first player in causing the cardinal motor symptoms in the disease.”

The study appears in the current issue of the journal Brain .

Shattering progression

The progression of Parkinson’s disease involves distinct stages, and the timeline can vary significantly among individuals. The typical stages of Parkinson's, as outlined by the Parkinson's Foundation , can help patients understand the changes as they occur.

The disease impacts people in different ways, and not everyone will experience all the symptoms or experience them in the same order or intensity. Some may experience the changes over 20 years or more; for others, the disease advances rapidly.

The progression of the disease is influenced by a combination of genetic and environmental factors. Following a diagnosis, many individuals experience a good response to medications such as levodopa, and this optimal time frame can last for many years.  Over time, however, modifications to medication are often needed and symptoms may intensify.

The prevalence of Parkinson’s has doubled in the past 25 years, which may be related to population growth, aging, genetic predisposition, lifestyle changes and environmental pollution.

A fresh perspective

The tau protein accumulates in two regions: the substantia nigra and putamen, both part of the basal ganglia in the brain. The substantia nigra is responsible for the production of dopamine, which is critical for modulating movement, cognitive executive functions and emotional limbic activity.

The putamen, a component of the dorsal striatum, is involved in movement initiation, selection and decision-making, as well as learning, memory, language and emotion. Dysfunction in the putamen can contribute to various disorders, particularly those related to motor function.

A wide range of physical and mental symptoms characterize Parkinson’s disease. These include: rhythmic tremors, often beginning in a limb, such as the hand or fingers; slowness of movement, which can lead to difficulty in performing simple tasks; muscle stiffness or rigidity; and difficulties with balance.

In addition to these physical symptoms, Parkinson's disease can also cause various mental and emotional changes, including depression and anxiety, sleep disorders, memory difficulties, fatigue and emotional changes.

Brain traces of disease

The scientists conducted the study using postmortem brain tissue from older adults who had experienced different degrees of motor impairment. The research analyzed brain tissues from individuals with no motor deficits, mild motor deficits with and without Lewy pathology in the nigral region of the brain, and from individuals clinically diagnosed with Parkinson's disease.

Lewy bodies are abnormal aggregates of the protein alpha-synuclein that accumulate in the brain, and they are a hallmark of several neurodegenerative disorders, including Parkinson’s and dementia with Lewy bodies.

In the case of Parkinson’s, Lewy bodies are primarily found in the substantia nigra, a region of the brain that is crucial for movement control, which leads to characteristic motor symptoms such as rigidity, tremors and bradykinesia (slow movement).

The study focused on a cohort of subjects with mild motor impairments — not pronounced enough to diagnose Parkinson’s, but still significant. Dividing these subjects based on the presence or absence of α-synuclein, researchers found that tau pathology was a common denominator.  

The researchers observed that the brain tissue associated with minimal motor deficit demonstrated similar accumulations of tau to those with advanced Parkinson’s, suggesting that tau's role occurs early in the disease's evolution. These findings open doors to earlier diagnosis and intervention, potentially slowing or altering the disease's progression.

The research also sheds light on parkinsonism, a condition that mimics Parkinson’s disease symptoms but is distinct in its underlying mechanisms. The study suggests that tau pathology in the nigrostriatal region of the brain is a shared characteristic, offering a new lens through which to view and treat various forms of parkinsonism.

The findings also underscore the potential of targeting tau pathology as a therapeutic approach in Parkinson’s disease. Because tau aggregation correlates with motor deficits and degeneration of dopamine-producing regions of the brain, interventions aimed at reducing tau accumulation could offer new hope for altering the disease's trajectory.

Kordower is joined by researchers from Neurodegenerative Diseases Research Unit, Biogen, Cambridge, Massachusetts; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, Maryland; Neurology, School of Medicine, Georgetown University Medical Center, Washington, D.C.; Department of Neurology, University of Alabama at Birmingham; and Pacific Parkinson’s Research Centre and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver.

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New Targets and New Technologies in the Treatment of Parkinson’s Disease: A Narrative Review

Nicola montemurro.

1 Department of Neurosurgery, Azienda Ospedaliera Universitaria Pisana (AOUP), University of Pisa, 56100 Pisa, Italy

Nelida Aliaga

2 Medicine Faculty, Austral University, Buenos Aires B1406, Argentina; [email protected] (N.A.); moc.liamg@raircseadnama (A.E.)

Pablo Graff

3 Functional Neurosurgery Program, Department of Neurosurgery, San Miguel Arcángel Hospital, Buenos Aires B1406, Argentina; moc.liamtoh@ffargep

Amanda Escribano

Jafeth lizana.

4 Department of Neurosurgery, Hospital Nacional Guillermo Almenara Irigoyen, Lima 07035, Peru; moc.liamg@anazilhtefaj

5 Medicine Faculty, Universidad Nacional Mayor de San Marcos, Lima 07035, Peru

Parkinson’s disease (PD) is a progressive neurodegenerative disease, whose main neuropathological finding is pars compacta degeneration due to the accumulation of Lewy bodies and Lewy neurites, and subsequent dopamine depletion. This leads to an increase in the activity of the subthalamic nucleus (STN) and the internal globus pallidus (GPi). Understanding functional anatomy is the key to understanding and developing new targets and new technologies that could potentially improve motor and non-motor symptoms in PD. Currently, the classical targets are insufficient to improve the entire wide spectrum of symptoms in PD (especially non-dopaminergic ones) and none are free of the side effects which are not only associated with the procedure, but with the targets themselves. The objective of this narrative review is to show new targets in DBS surgery as well as new technologies that are under study and have shown promising results to date. The aim is to give an overview of these new targets, as well as their limitations, and describe the current studies in this research field in order to review ongoing research that will probably become effective and routine treatments for PD in the near future.

1. Introduction

Parkinson’s disease (PD) is a chronic, progressive, and debilitating neurodegenerative disease that stands as the second most common neurodegenerative disease and affects about 1% of the population aged above 55 years old [ 1 , 2 ]. PD is the most common cause of “parkinsonism”, a syndrome manifested by rest tremor, rigidity, bradykinesia, and postural instability [ 3 ]. These four clinical presentations are commonly present; however, they do not occur long after the disease arises and therefore, they are not included in the Movement Disorder Society (MDS) diagnostic criteria for PD [ 4 , 5 , 6 , 7 , 8 ]. In PD the main neuropathological finding is substantia nigra pars compacta degeneration because of the accumulation of Lewy bodies and Lewy neurites [ 2 , 9 ] and subsequent dopamine depletion [ 10 ].

Deep brain stimulation (DBS) is a technique in which one or more multiple-contact electrodes are implanted in specific brain regions. These electrodes are connected to a subcutaneous implantable pulse generator from which the depolarization, re-polarization and conduction patterns of the neurons’ action potential are electrically modulated. Typically, high frequency stimulation (more than 100 Hz) mainly decreases the ipsilateral discharges from the subthalamic nucleus (STN), but there is also a decrease in contralateral STN nucleus firing [ 11 , 12 , 13 , 14 ]. Moreover, DBS is a three-dimensionally complex phenomenon, and consequently, a decrease in the action potentials in related nearby areas has been reported [ 15 , 16 ]. Even though there are paradoxical in vitro results published in the literature, it is probably because in vitro samples are disconnected from their afferents, so they do not have the chance for orthodromic stimulation [ 17 , 18 ]. However, aside from the DBS effects, it appears to be transient, with several articles suggesting that DBS as well as new technologies may induce long term changes in neuronal properties [ 19 , 20 , 21 ]. Neurochemical differences (GABA, glutamate, DA, cGMP, mGLUR, DR1/DR2) and induction of synaptic plasticity have also been observed in the target and in other related deep nuclei, structures, and the cortex itself [ 16 , 19 , 20 , 21 , 22 , 23 ].

Currently, the FDA (Food and Drug Administration) has approved modulation by DBS in the subthalamic nucleus (STN), the internal globus pallidus (GPi) and the ventralis intermedius nucleus of the thalamus (Vim). Targeting just these classical targets is insufficient for improving the entire wide spectrum of symptoms in PD (especially the non-dopaminergic ones), and none are free of the side effects which are associated not only with the procedure, but with the targets themselves. However, new targets and new technologies that could potentially improve the motor and non-motor symptoms of PD are currently proposed in the literature and are here discussed.

2. Overview of Basal Ganglia Functional Anatomy

The classical model of the basal ganglia includes both the direct and indirect pathways [ 24 , 25 , 26 ]. Both pathways are modulated by dopamine from the SNc (nigrofugal pathway) which sends projections to the posterior putamen, which in turn sends GABA projections back to the SNc. In addition, the motor cortex, the somatosensory cortex and the STN send glutamatergic fibers to the SNc [ 24 , 26 , 27 ]. However, there is evidence that the striatofugal pathways (direct and indirect) can no longer be considered dual, due to complex and extensive networks with advanced patterns of bridging collaterals ( Figure 1 ) [ 28 ]. This provides straightforward evidence of the overlap and the delicate balance between both pathways [ 28 , 29 ]. Additionally, it is known that there are different functional regions in the striatum and the pallidum for the sensorimotor, associative, and limbic components [ 30 ]. For example, the head and the tail of the caudate have mainly associative fibers, while the putamen has mostly sensorimotor connections. Additionally, the ventral striatum has predominantly associative fibers and is also related to the limbic system [ 30 , 31 ]. However, in the end it is difficult to draw a boundary line between the dorsal and the ventral striatum, as well as between the functionality of each one [ 30 ].

This figure shows a coronal section of the basal ganglia circuit with emphasis on its complex connections. Illustrated by J. Lizana.

The pallidofugal pathway is related to symptoms such as tremor and stiffness [ 32 ] and it is also known that 90% of cells that make up the GPi are motor neurons which connect to the PPN, ventral and CM/PF nuclei of the thalamus; however, there are 10% of limbic neurons that reach the lateral habenula [ 25 ]. Traditionally, it was believed that in the pallidofugal pathway the bipolar neurons at the lateral GPi would send their axons to the thalamus through the lenticular fasciculus and the ansa lenticularis, while neurons at the medial GPi would only send their axons through the lenticular fasciculus, and the GPe would send its efferents through the subthalamic fasciculus to reach the STN ( Figure 2 a) [ 25 , 33 , 34 ]. Nevertheless, there is evidence that the pallidofugal pathway fibers from the dorsal part of the GPi travel through the lenticular fasciculus, then pass between the STN and the ZI to finally reach the ventral part of the thalamus, while the fibers from the intermediate part of the GPi travel through the pallidum subthalamic tract and reach the lateral STN side [ 25 , 33 , 35 ]. Finally, the axons from the ventral part of the GPi travel through the ansa lenticularis then connect to the SN and continue to the brainstem through the fasciculus Q of Sano or the pallido tegmentalis, while other fibers of the ansa lenticularis turn dorsally to reach the thalamus through the thalamic fasciculus ( Figure 2 b) [ 35 ]. In the case of the GPe, there is a description of a direct projection to the frontal regions of the cerebral cortex, the caudate and the putamen [ 34 , 36 ].

Figure ( a ) depicts the classical pallidofugal pathways, while Figure ( b ) illustrates some changes in the recent understanding of how the Globus pallidus communicates with other basal ganglia structures. Illustrated by J. Lizana.

With regards to the cerebral cortex, its connections with the basal ganglia are also well known (Corticofugal pathway). For instance, the prefrontal cortex has connections with the caudate’s head; however, the dorsolateral prefrontal cortex and the pre-supplementary motor area are related to the anterior putamen [ 2 , 26 ]. Meanwhile, the limbic cortical areas that are connected to the ventral striatum and the motor cortex by the corticostriatal pathway, reach the posterior putamen [ 2 , 26 , 30 ]. The study of these pathways resulted in the identification of the glutamatergic hyperdirect cortico-subthalamo-pallidal circuit which plays a very important role in DBS procedures [ 24 , 37 ]. Furthermore, functional images have provided evidence of cerebellar activation in a wide variety of motor and non-motor processes [ 38 , 39 , 40 , 41 ]. It has been proved that a lot of cortical areas and basal ganglia nuclei, which are targets of cerebellar output, also project back onto the cerebellum ( Figure 3 ) [ 40 , 42 , 43 ]. STN DBS may not only normalize the functional activity of the associative and limbic cerebellar cortices and decrease the activity of Purkinje cells with consequent disinhibition of the cerebellar nuclei, but could also improve some non-motor symptoms [ 40 , 44 , 45 ]. There is also evidence that STN DBS in dystonia, Tourette syndrome and PD results in decreased cerebellar hypermetabolism and symptom improvement [ 40 ]. Research in functional neuroanatomy has allowed critical advances in the development of new devices as well as the possibility of new targets.

A sagittal section of the brain, trunk and cerebellum shows the complex connections between basal ganglia and cerebellum. AMY, Amygdala; BC, Brain cortex; CC, Cerebellar cortex; CiC, Cingulate cortex; CN, Caudate nucleus; DN, Dentate nucleus; FN, Fastigial nucleus; GPe, External globus pallidus; GPi, Internal globus pallidus; IN, Interpositus nucleus; NAcc, Nucleus accumbens; NBM, Nucleus basalis of Meynert; PN, Pontine nuclei; PUT, Putamen; RN, Red nucleus; STH, Subthalamus; THA, Thalamus. Illustrated by J. Lizana.

3. New DBS Targets

3.1. pedunculopontine nucleus.

The pontine peduncle nucleus (PPN) is a motor center of the trunk that is related to the initiation and modulation of the gait and receives afferents from the cortex, the central core, the trunk, and the medulla [ 46 , 47 ]. The PPN consists of the Cholinergic Pars Compacta (PPNc) and the Pars Dissipatus (glutamatergic and cholinergic) [ 47 ] and it is located medially to the middle lemniscus and laterally to the decussation of the superior cerebellar peduncle. Its rostral portion is posterior to the SN and the RRF, while its caudal pole meets the reticular formation, the cuneiform nucleus, and the locus coeruleus [ 48 ]. It has been observed that low-frequency stimulation of the PPN (bilateral or unilateral) inhibits the GABAergic neurons of this nucleus, which allows their activation and increases movement [ 47 , 49 , 50 ]. It is important to note that this nucleus may be involved in PD. However, the stimulation of this area may compromise adjacent structures such as the caudal portion of the mesencephalic reticular formation [ 47 , 48 , 49 , 51 ]. In many cases, DBS of the PPN has had good results on different aspects of the gait and appears to be a safe target [ 51 ]. Nevertheless, this effect is not uniform in all studies, nor in all patients [ 52 , 53 , 54 ].

3.2. Zona Incerta

The caudal zona incerta is a known target and is part of a region called the posterior subthalamic area, which is located posteromedial to the STN, inferior to the thalamus and lateral to the red nucleus [ 9 ]. It has been observed in studies carried out in patients with STN-DBS, that stimulation of this area and the adjacent ones (pallidothalamic fibers) improves the results, which contrasts with patients where only the STN is stimulated, thus developing interest in the surrounding structures (the zona incerta) as a possible therapeutic target since it is a unique GABAergic link between the basal ganglia output nuclei, the cerebello-thalamo-cortical loop and the brainstem nuclei [ 55 , 56 , 57 , 58 ].

Due to their interconnections with the basal ganglia and the cerebellum ( Figure 1 ), stimulation of the zona incerta (incerto-thalamic fibers) and the bundles that cross this area (the nigrothalamic fibers, the incerto-pallidal bundle, the pallidal-thalamic pathway and the cerebellar-thalamic tract) improves, importantly, symptoms such as essential voice tremor compared to STN stimulation [ 46 , 59 ], and also results in decreases in bradykinesia, rigidity, ataxia and abnormal muscle activities [ 60 , 61 ]. Moreover, stimulating the ZI and adjacent areas decreases the required dose, and reduces the adverse effects, of dopaminergic medication [ 62 ]. Other points in favor of this target are that it is relatively easy for neurosurgeons to leave the deep ventral DBS contact in the caudal ZI, and that long term studies have shown that the ZI does not develop tolerance; however, Vim DBS did provide better outcomes [ 61 , 63 ]. However, it is necessary to highlight that it can cause or exacerbate dyskinesia, dysarthria, and can also alter pleasure-seeking behavior [ 60 , 64 ]. There are limitations to these findings with regards to it being a new target so it is a procedure rarely performed and with few studies on the subject, as such, we cannot define conclusions [ 61 , 63 ].

3.3. Thalamic CM/Pf Complex

The thalamus as a target (Vim) for DBS was the first to be studied and applied in clinical practice and demonstrated adequate control of the tremor at rest [ 65 ]. The centromedian/parafascicular complex (CM/Pf) is located in the posterior intralaminar thalamus [ 66 , 67 ]. It is an important center for sensory, limbic and motor processing association due to its extensive connections with the cortex, the basal ganglia and the brainstem [ 66 ]. It has been observed in patients whose dyskinesia improves that the thalamic electrode is closer to the CM/Pf than to the Vim [ 67 , 68 ]. Similarly, clinical improvement has been highlighted in tremor and freezing of gait, motivating interest in its role in DBS surgery [ 69 , 70 ]. Although it does not affect extrapyramidal symptoms with the same intensity as DBS of the STN, it seems to be a better target than the Vim and it opens up the possibility of a synergistic and complementary effect with other targets for patients with difficult-to-control symptoms [ 67 , 69 , 70 , 71 ].

3.4. Substantia Nigra Pars Reticulata (SNr)

The midbrain locomotor region is a functional territory that appears to be comprised of both the cuneiform nucleus and part of the PPN and is directly influenced by GABAergic nigro-tegmental projections from the SNr in addition to the supplemental motor cortex [ 72 , 73 ]. This relationship of the SNr with the ponto-mesencephalic and spinal structures motivated experimental studies where it was observed that both its unilateral and bilateral stimulation (and in many of these cases combining its effect with the stimulation of the STN), could favor the improvement of axial symptoms related to the onset of gait in patients with PD [ 72 , 74 ]. Furthermore, an improvement has also been noted in the axial symptom subsection of the UPDRS scale, thus constituting a potential tool for the treatment of postural instability and freezing of the gait [ 73 , 75 , 76 ]. However, psychiatric side effects (acute depression, hypomania and mania) have been reported in a variable way and are possibly related to its limbic connections [ 73 ].

3.5. Multitarget

Multitarget therapy is a novel and interesting option that involves more than one anatomical objective for patients in whom the most common targets such as STN or GPi, by themselves, are insufficient for controlling the symptoms of the disease, mostly, non-dopaminergic symptoms such as gait, balance impairment and cognitive decline [ 46 , 77 , 78 ]. As detailed in the previous sections, the use of new targets such as the PPN, the ZI, the SNr and the thalamus for DBS is under investigation [ 54 ]. These options are open to different therapeutic scenarios for the management of complex cases. If their effectiveness is demonstrated, it is most likely that they will not replace the classical targets but will be used as adjuvants in selected cases [ 79 ]. Similarly, it is possible to combine the stimulation of two classical targets such as the STN and the GPi to obtain better results [ 80 ]. The development of multitarget therapy is based on the improvement of surgical times, technological progress and the clinical benefits associated with biochemical changes in areas other than the STN for the legitimate control of clinical signs that cannot be controlled with classical DBS targets [ 70 , 80 ]. Candidates for multitarget therapy are patients with involuntary movements who are reluctant to decrease their dose of drugs; patients with severe tremor whose response to STN-DBS progressively decreases; patients freezing in ON periods; and even patients with mild cognitive impairment whose eligibility for STN-DBS may be in doubt [ 80 ].

One of the advantages of GPi/STN-DBS in PD is that it offers greater control of neuropsychiatric symptoms. [ 46 , 70 ] Currently, a GPi/STN-DBS strategy is more than an eligible approach for those cases where there is profound and medically refractory functional impairment [ 78 , 81 ]. GPi/STN-DBS has shown favorable outcomes; however, its effect has been seen to decrease over time. For this reason, more evidence is needed to fully understand the advantages and limitations of this dual stimulation [ 78 ]. Treating multiple targets with DBS is limited by its higher costs, the prolonged inconvenience of surgery due to its slower result, greater probability of complications, and the requirement of multidisciplinary and highly specialized healthcare staff for peri- and post-operative management [ 70 , 77 ]. This review is susceptible to changes through time, as technology and science become more advanced and new research will be reported in the near future.

4. Non-Invasive and Minimally Invasive Treatment

4.1. endovascular approach.

The use of endovascular devices (with cable or without cable) with the ability to record brain activity and stimulate adjacent tissue (STENTrodes) has emerged as an alternative among mechanisms of deep stimulation with minimal invasion for the treatment of PD, essential tremor, epilepsy, severe paralysis and many other diseases [ 82 , 83 ]. There is a wide variety of catheters, guide catheters, microcatheters and micro guides, among others, which facilitate the release of the devices in the desired location [ 82 , 84 ]. The endovascular routes for the release of the device can be by a transarterial or transvenous route [ 83 ]. However, the anatomical variations of the vascular structures are a limitation for the adequate positioning of the device, since precise planning for the identification of an accessible vascular structure (vessels with a diameter greater than 1 mm are more accessible) closest to the target is essential. Angiography and MRI protocols have taken on a greater relevance for the elaboration of probabilistic maps in order to improve the accuracy of the device placement [ 83 , 85 , 86 ]. Only some structures such as the nucleus accumbens, fornix, subcallosal cortex of the cingulum, dentato-rubro-thalamic tract, subthalamus and pontine peduncle nucleus, among others, are susceptible to stimulation by this route due to their vascular proximity [ 83 , 87 ] ( Figure 4 ). It should be noted that the possibility of performing the procedure with the patient awake allows for evaluation of the procedure and observing whether the result is the desired one [ 88 ]. Although endovascular therapy has an encouraging future due to new and continuous advances, it must be considered that there are potential side effects depending on the location of the device, ranging from psychiatric disorders (due to proximity to the limbic system) to autonomic problems (due to proximity to the hypothalamus), and also those of the procedure such as intracranial hemorrhage and arterial or venous thrombosis by the intraluminal device (with SHIELD technology the thrombogenicity of the devices is reduced) [ 82 , 83 , 87 , 89 ].

This figure shows some theoretical locations (superior sagittal sinus, internal cerebral vein and basal vein of Rosenthal) of STENTrodes which can be placed by the endovascular transvenous approach to stimulate the cortex, thalamus or brainstem nuclei. Illustrated by J. Lizana.

4.2. Non-Invasive Transcranial Stimulation

Non-invasive transcranial stimulation is based on beta oscillatory activity (14–35 Hz anti-kinetic activity) that occurs at the level of the motor cortex and its connections with the basal ganglia (predominantly with the subthalamus and the GPe) [ 90 , 91 , 92 ]. These connections are exacerbated (excessive beta synchronization) in patients with PD [ 91 , 92 , 93 , 94 ]. This abnormal activity occurs mainly during involuntary tonic contractions and decreases with voluntary motor activity (beta desynchronization), as well as with pharmacological and surgical treatment [ 91 , 92 , 93 , 94 ].

Currently, there are two techniques known as “Non-invasive transcranial stimulation”: The first one, Transcranial Current Magnetic Stimulation (TMS) and the second one, Transcranial Current Stimulation (tCS) [ 95 , 96 ]. Both have proved to have a good efficacy rate in the modulation of cerebral activity [ 95 , 96 , 97 ]. One of the advantages of this non-invasive technology over DBS is that it can target cortical and subcortical structures; therefore, it can reach remote locations from the stimulation site [ 96 , 98 ]. It should also be mentioned that DBS is an invasive procedure, consequently, it goes hand in hand with some complications, such as infection, limited duration of electrical components, neural immune system reactions, and the need for periodic battery replacement [ 99 , 100 , 101 , 102 ]. One of the limitations of TMS is that this device is large and heavy, whereas tDCS is light and small, which makes it more feasible since it is a treatment that does not require hospitalization and the sessions can be performed at the patient’s home [ 97 , 103 ]. Cost is another big difference, with TMS systems costing between $20,000 and $100,000, while tDCS devices have prices ranging from $400 to $10,000 [ 95 , 97 , 104 ].

4.2.1. Transcranial Magnetic Stimulation (TMS)

TMS is a well-tolerated and painless brain stimulation technique in which a strong and rapidly changing electromagnetic field is generated [ 95 , 97 , 103 , 105 ]. This electromagnetic field induces strong and short-lived electrical currents, which initiate action potentials in both the cortex and subcortical white matter [ 96 , 97 , 105 ]. The application of repetitive transcranial magnetic stimulation (rTMS) is able to induce lasting changes in cortical excitability, which represents a promising tool against neuropsychiatric alterations and motor symptoms in PD [ 98 , 104 , 106 ]. Unlike TMS, rTMS appears to be more effective in stimulating the association cortex [ 107 ]. Presently, TMS has a larger number of published studies demonstrating its safety in terms of effects on brain anatomy and biochemistry, than does tDCS [ 97 , 105 ]. Other studies being conducted, which link rTMS with an improvement in non-motor symptoms in PD such as cognitive dysfunction, speech difficulty and depression, show mixed results [ 105 , 107 ]. However, its greatest risk is the induction of seizures [ 108 ]. Preclinical data on the safety of TMS is still very limited, and rTMS protocols are needed to use this technology as a routine treatment for PD [ 95 , 98 ].

4.2.2. Transcranial Current Stimulation—Transcranial Direct Current Stimulation (tDCS)

TCS has re-emerged as a form of non-invasive modulation of spontaneous neuronal activity by applying a weak electrical current (1–2 mA) through the placement of two or more electrodes on the scalp, allowing regulation of neuronal membrane potentials (changes in discharge probability), changes in neurotransmitters, glia, and micro vessels [ 109 ]. In other words, it provides neuronal plasticity, shown by the generation of long-term synaptic potentiation (objectified by the increase in brain derived neurotrophic factor (BDNF) secretion and TrkB activation) when combined with repetitive low-frequency synaptic activation [ 110 ]. Transcranial direct current stimulation (tDCS) affects the motor symptoms of the disease, with the most prominent results related to rehabilitation. However, its usefulness is limited due to its weak effects, high variability, and lack of consensus in protocols, with medication status being a key cofounder in determining the level of efficacy [ 111 ].

4.2.3. Transcranial Current Stimulation—Transcranial Stimulation with Alternating Current (tACS)

Recent innovations in transcranial alternating current stimulation (tACS) offer new areas of research [ 111 ]. This is a variant of direct cranial stimulation and consists of the interference of sinus waves for the modulation of brain oscillations (physiological brain activity in an area) [ 109 , 111 ]. It has been observed that tACS has a different effect on healthy people compared to those with PD due to its effect on beta synchronization [ 92 , 112 ]. tACS seems to produce an improvement in motor symptoms in people with PD, which is further enhanced when associated with a closed loop system [ 92 ]. Furthermore, when this device stimulates the cerebellum, it also results in the modulation of parkinsonian tremor [ 113 ]. In addition to this, there is evidence that, like tDCS, it not only modulates brain activity, but also seems to generate cortical neuronal plasticity [ 114 , 115 , 116 ].

4.3. Non-Invasive Focused Ultrasound

Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel, non-invasive procedure for symptomatic treatment of PD [ 117 , 118 ]. Two types of focused ultrasound therapy are recognized. The first one is called non-ablative: this technology has potential uses in pain neuromodulation, epilepsy, and is also seen as a new strategy to allow the passage of medication through the BBB, for instance, biological-genetic treatment in PD [ 117 , 119 ]. The second one is ablative ultrasound, in which two varieties are differentiated according to the frequency used. High intensity focused ultrasound (HIFU) produces thermal ablation in small brain targeted areas (therapeutic sonication) [ 118 , 120 ]. This technology enables accurate targeting by using a real-time MRI for morphological and thermal monitoring [ 120 , 121 ]. On the other hand, ablation at low frequencies is due to a fast change in the targeted tissue pressure, forming gas–vapor filled cavities. These cavitation bubbles oscillate at large amplitudes and exert shear stresses on the surrounding tissue, causing the mechanical cell membranes to tear (histotripsy) [ 119 , 122 , 123 ].

The use of HIFU in the Vim nucleus has been approved by the FDA for the treatment of tremor in patients with PD [ 117 , 120 , 124 ]. Candidate patients for Vim ablation are those with very asymmetric symptoms, who are not able to have or do not want surgery or implants, but does not including patients with refractory tremor. Exclusion criteria are severe bilateral axial symptoms, severe dyskinesia, cognitive impairment, or psychiatric illness [ 117 ]. Although unilateral ablation of the Vim seems to be effective, it has transitory side effects such as weakness, gait, and speech disturbances [ 120 ]. The STN is a potential target for MRgFUS; however, due to few studies being available, it cannot be considered as strong evidence. This procedure has a high rate of adverse effects, with gait instability being the most frequent; however, all are mostly transient [ 117 , 120 , 125 ]. Similarly, the results of GPi ablation in patients with PD is little but encouraging due to the effects its ablation has on dyskinesias, as well as the improvement of PD symptoms in off-L-dopa state patients [ 117 , 126 ]. Furthermore, challenges lie ahead in treating this target due to its proximity to the optic nerve and being able to correctly target the ultrasound rays on the treatment area [ 118 , 127 ].

The advantages of MRgFUS over DBS are that this non-invasive technology does not carry any risk of infection or hardware failure, and post-operative programming is not required as the effect is achieved immediately at the end of the procedure [ 120 , 128 ]. What is more, this procedure does not include any kind of brain penetration, therefore, it does not have the complications associated with foreign object implantation [ 120 , 129 , 130 ]. Gamma knife use also effectively suppresses tremor but is limited by the latent effects of radiation and the inability to target intraoperatively [ 130 ]. Nevertheless, some disadvantages of MRgFUS lie in its local effects, such as headache, scalp burns, and bone necrosis [ 123 ].

5. Regenerative Medicine in Parkinson Disease

Currently, none of the pharmacological or surgical treatments can cure or modify the neurodegeneration process that occurs in PD [ 131 , 132 ]. Furthermore, it is known that the current management of PD is insufficient and costs billions to the world economy. In the USA alone, the cost of PD is 35 billion annually and it is estimated that by stopping its progression, the economic benefit would be almost 450,000 dollars per patient [ 133 ]. Regenerative medicine has been progressively developed in recent decades with the aim of reconstructing and restoring the functionality of highly sophisticated neural circuits (connectome) that are lost in PD [ 131 , 132 , 134 , 135 ]. Technological progress in cell engineering, cell programming, immunomodulation, tissue engineering, biomaterials, gene therapy, and stem cells has allowed the development of several studies that project a promising future in this type of biological therapy [ 136 , 137 , 138 , 139 , 140 ].

5.1. Gene, Cell, and Tissue Regenerative Therapies

Autologous or heterologous cell transplantation with neural differentiation potential has shown satisfactory results in animals and humans [ 136 , 141 , 142 ]. Different cell types can be divided into these groups: fetal mesencephalic cells, adrenal medullary cells, carotid body cells, sympathetic ganglia cells, and retinal pigmentary epithelial cells [ 142 , 143 ]. Human fetal mesencephalic tissue grafts are the ones with the most evidence and the greatest success (documented improvement of motor symptoms) to date [ 144 , 145 , 146 ]. The objectives of this type of therapy are the survival of dopaminergic cells, afferent and efferent synaptic integration, and adequate and controlled dopamine release, in addition to the clinical improvement of patients [ 136 , 141 , 147 ]. There are reports of patients in whom the presence of transplanted cells has been demonstrated up to 24 years later; however, their potential susceptibility to degeneration is still not clear [ 145 , 148 ]. The problems with the clinical studies involving fetal mesencephalic cells include: the heterogeneity of the cells, in most cases the transplant has not been performed in the SNc region but in the striatum, there is a well-known limitation in the availability of fetal tissue, cells do not always differentiate as expected, it has been observed that the grafts are not made up purely of dopaminergic cells, this kind of procedure often requires immunosuppression, and there are underlying ethical considerations [ 142 , 149 , 150 , 151 ]. Another risk in the use of stem cells is the neoformation of tumors and the development of graft-induced dyskinesia (GID) [ 152 , 153 , 154 ].

There are other sources of cells with potential dopaminergic differentiation such as embryonic stem cells (ESC), induced pluripotential stem cells (iPSC), neural precursor cells (NPC), mesenchymal stem cells (MSC), and direct neuronal reprogramming [ 152 , 155 , 156 ]. ESCs come from early-stage embryos, which implies ethical problems, limited availability, and they have a significant risk of tumor development [ 152 ]. Knowledge of cell de-differentiation techniques as well as advances in neurodevelopment have allowed the generation of iPSCs with greater similarity to dopaminergic neurons and with a lower oncological risk [ 156 , 157 ]. NSC can be induced from iPSC and because of their limited differentiation capability they have less oncogenic likelihood [ 158 ]. On the other hand, MSCs have a more limiting potential for neural differentiation but have an immunomodulatory effect that counteracts neurodegeneration [ 159 ]. Problems with earlier grafts have generated an increased interest in neuronal reprogramming, in which virus vectors, microRNAs, or transcription factors can be used to alter the gene expression in astrocytes in order to generate dopaminergic neurons [ 138 , 140 ].

Despite advances in cell restoration, there is a gap to recover the lost functionality, that is, the development of new and appropriate neuronal circuits which maintain the dopaminergic function [ 139 , 160 , 161 , 162 , 163 ]. Axonal growth over long distances, its directionality, and the reinnervation of the correct target continue to be a matter of investigation [ 160 , 164 , 165 , 166 , 167 ]. Nowadays, chemoattractant factors are being used in the striatum to promote the restructuring of the nigrostriatal pathway [ 165 ]. Other strategies include the use of embryonic striatal tissue, renal tissue, kainate injections, and overexpression of GDNF (glial cell line-derived neurotrophic factor) in the striatum by virus vectors [ 168 , 169 ]. The development of new micro biomaterials has allowed the creation of scaffolds for grafts, that not only protect and promote the graft growth but can also be implanted in the form of neural networks that stimulate the nigrostriatal pathway and favor its restoration [ 139 , 160 , 170 ]. Finally, there is a potential risk that any cell or tissue engineering strategy may succumb to the underlying pathology and degenerate in a similar way to the original tissue, so developing new grafts resistant to different stress factors is a new objective [ 151 , 171 , 172 ].

5.2. Optogenetic Therapy

The lack of control over the delimitation of the stimulated area can lead to undesirable results [ 173 , 174 ]. Due to this problem, optogenetic therapy has emerged as an interesting option to avoid side effects due to the stimulation of structures adjacent to the target [ 175 ]. This therapy consists of the use of genetically altered viruses with the aim of modifying neuronal genes (the gene for an ultra-fast opsin called Chronos is packaged in the adeno-associated virus type V with a CaMKII promoter for a local effect on the subthalamic nucleus) and making them susceptible to excitation or inhibition by light, so that the desired effect is generated in a more controlled way in each area [ 171 , 172 , 173 , 174 , 175 ]. Optogenetic therapy opens a way for us to understand synaptic and circuit properties on a mechanistic level [ 176 , 177 ]. Favorable results in several animal studies lead us to believe that this therapy could be an important research tool for future DBS-based therapies, leading to symptoms being resolved, and not masking them [ 174 , 178 ]. However, to date this technique is not yet feasible in humans and suffers from other limitations such as light stimulation parameters (duration, frequency, and intensity of stimulation) which must be managed carefully to avoid problems such as depolarization blocks or rebound excitation [ 177 , 179 , 180 , 181 ]. We hope that one day this could be a viable treatment for movement disorders.

6. Discussion and Conclusions

Research into functional anatomy as well as clinical trials have allowed a better understanding of the basis, benefits, and limitations of DBS procedures [ 24 , 26 , 38 ]. The most common scope of studies in PD is directed towards motor symptoms [ 132 ]. However, non-motor symptoms are as relevant as these but less studied and, due to their great impact on quality of life, they require more intensive research [ 73 , 132 ]. Currently, progress in the development of devices is reflected in increasingly personalized treatments and the approach of new targets [ 46 , 77 ]. Although most of these targets require more evidence for their widespread use, they open the possibility of being associated with classical targets to achieve better symptom control [ 79 , 80 ]. One of the main disadvantages of DBS is the high cost involved while newer devices appear to be cheaper [ 92 , 104 , 133 ]. In addition, several of these new devices offer the advantage of being minimally invasive or non-invasive at all [ 85 , 87 , 105 ].

Accelerated advances in biological therapy, gene therapy, cell engineering, tissue engineering, and biomaterials have made it possible to propose new therapeutic options with the potential to modify the course of the disease [ 134 , 140 , 160 ]. Even though several studies have shown encouraging long-term results with the use of embryonic or fetal human cells, the limitations and risks of this type of graft have motivated the development of techniques for the induction of new cells with dopaminergic potential [ 151 , 156 , 157 ]. Nevertheless, we must consider that both the management of fetal or embryonic tissue, as well as genetic manipulation at the cellular or viral level, entail ethical considerations and risks [ 152 , 155 , 169 ]. The development and use of biomaterials in the peripheral nervous system is currently quite widespread; however, the central nervous system constitutes a more complex area for their use. The accuracy in the design, its microstructure that tries to reproduce the neural circuits, and the advantages shown in the studies are encouraging [ 164 , 169 ]. Most current studies are focused on technological advances, but this should not be separated from the study of functional micro neuroanatomy, since the integration and deepening of both will allow for better results.

There is parallel improvement in regenerative and non-regenerative treatment. Non-regenerative treatment seeks to improve the performance, invasiveness issues, and duration of its devices [ 46 , 77 , 96 ]. However, it has not been shown to affect the disease progression [ 118 ]. Merely stopping its progression would generate a major impact, but current initiatives go beyond that and seek to regenerate the tissue and lost connections, that is, to cure it [ 133 , 160 ]. As described, the new therapeutic options also have limitations and problems, but under the same logic of multitarget treatment, with the wide range of current options, studies of multimodal or hybrid management in PD should be considered. We believe that the treatment of PD will no longer be symptomatic related in due time and that the future directions of surgical management of PD are towards regenerative neurosurgery. We have described the current studies and ongoing research in PD in order to review the treatments that may become effective and safe in the near future for the treatment of PD.

Funding Statement

This research received no external funding.

Author Contributions

Conceptualization, J.L., N.A., P.G. and N.M.; methodology, N.A. and N.M.; validation, J.L., N.A. and A.E.; formal analysis, J.L., N.A. and P.G.; writing—original draft preparation, J.L., N.A., P.G. and N.M.; writing—review and editing, J.L., N.A., A.E. and N.M.; visualization, J.L.; supervision, J.L., N.A. and N.M. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Conflicts of interest.

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Stacy was working as a doctor in her 20s when she developed a tremor that led to a Parkinson's diagnosis

Stacy Patterson was in her late 20s and training to be a surgeon when she developed a tremor in her left hand.

At first the right-hander dismissed the problem, putting it down to having too much caffeine and not enough food — a symptom of the long hours and hard work required of a junior doctor.

"Being stubborn and a doctor, I didn't really think much of it," she said.

But after her Brisbane flatmate — also a doctor — encouraged her to see a general practitioner, she found herself embarking on a year-long trail of medical scans and tests. Eventually, she was being diagnosed with early onset Parkinson's disease.

The diagnosis ended her dream of becoming a surgeon, specialising in obstetrics and gynaecology.

It's also made the future scarier than it might otherwise have been – for both Dr Patterson and her husband of seven months, Jeremy, who is an engineer.

"Every case of Parkinson's is incredibly different," Dr Patterson explained, with tears in her eyes.

"You don't know how fast you're going to progress. Some people do really, really well and some people don't.

"You don't know which one you're going to be – and that's terrifying."

Her husband has known about her Parkinson's since they started communicating through the dating app, Hinge, during the early stages of the pandemic.

"It was very refreshing to find somebody who was accepting of that," she said.

What is Parkinson's?

Parkinson's disease is a progressive movement disorder, characterised by degeneration of dopamine-producing nerve cells in a part of the brain called the substantia nigra.

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.

Some people develop what's called micrographia, which means their handwriting gets smaller.

Dr Patterson was born in Edmonton, Canada, growing up on the prairies and spending her summers camping in the Rocky Mountains.

It's the same city where actor Michael J Fox, another early onset Parkinson's disease patient, was born.

The Back to the Future and Family Ties star was just 29 when he was diagnosed with Parkinson's disease – and so was Dr Patterson, who is now 35.

But her similarities with the Canadian celebrity, and Dr Patterson's medical training at the University of Queensland, did little to expedite her diagnosis.

It would take about 12 months.

A fifth of patients are under the age of 50

Dr Patterson did not meet the usual Parkinson's disease medical profile, confounding her diagnosis.

"In medical school, you're taught that it affects men more than women, and it affects usually older people," she said.

"Even though I knew … that it is possible in young people, it was highly, highly unlikely, it's very rare."

Parkinson's Queensland chief executive Miguel Diaz said an estimated 18,000-20,000 Queenslanders have the condition.

On average, six new cases are diagnosed in the state every day.

About 20 per cent of those are young onset patients – those diagnosed under the age of 50 – but cases as young as Stacy and Michael J Fox are unusual.

What causes Parkinson's?

While scientists have identified dozens of genetic mutations linked to Parkinson's disease, and the condition can occur in families, causes in most cases remain elusive.

Multiple contributing factors are suspected.

For example, pesticide exposure has been linked to a small increased risk of developing the condition.

"Clusters do appear in rural and regional farming areas, for example," Mr Diaz said.

Dr Patterson's neurologist Alexander Lehn, who sits on the Parkinson's Queensland board, said rates of the disease are rising, and not only because of the aging population.

He said environmental pollutants may also be fuelling the increasing prevalence, but more research was needed to identify triggers in what is believed to be a complex interplay between genetics and other factors.

"We all want simple answers, but real-life reality is not that simple," Dr Lehn explained.

"Most likely, what we're going to find in the end, is you need a few hits to the system for most people to develop the disease."

In Dr Patterson's case, testing has so far failed to find any known genetic links, but that could change as research evolves.

Operation sees electrodes placed on brain

Dr Lehn held his patient's hand as she had deep brain stimulation two-and-a-half years ago at Brisbane's Princess Alexandra Hospital to treat some of her motor symptoms, including tremors.

Dr Patterson was awake as neurosurgeon Dr Sarah Olson operated to implant electrodes in her brain, attached to a battery-powered device inserted under the skin below her collar bone.

The device sends electrical pulses to stimulate key areas of the brain, affecting movement.

"It was my first time back in theatre for ages and it was incredibly comfortable being back there until I was bolted to the operating table, which was terrifying," Dr Patterson recalled, referring to the metal halo her head was placed in to ensure it didn't move during the procedure.

Dr Lehn talked to her throughout the operation, asking her to move her hands and other tasks to ensure the electrodes were placed in the optimal spots.

The surgery has reduced Dr Patterson's symptoms and allowed her to cut down on medication.

"It doesn't work for everybody," Dr Lehn said.

He explained deep brain stimulation is not a cure for the disease, nor does it slow its progression.

At this stage, science has produced nothing that can halt the condition or slow it down, although symptoms can be treated in many patients.

A new career path

Despite her diagnosis, Dr Patterson avoids reading too much about Parkinson's disease research.

She prefers to focus on her new career passion – forensic medicine.

Working for Forensic Medicine Queensland, she provides medical interpretations to coroners and courts relating to deaths in both hospitals and the community, assessing whether anything could have changed the outcome.

She also provides sexual assault examinations and trains other health professionals in how to perform them.

"It is working with a lot of women, as well as men, who are facing a terrible circumstance and it's good to be there," Dr Patterson said.

Nevertheless, she winces at any suggestion that she is successfully overcoming her Parkinson's disease diagnosis.

"I don't know so much as it's overcoming as just kind of adapting and living with your new reality," Dr Patterson said.

"I don't want people to judge their own journey by my own, because the hardest thing about being an advocate for a disease like Parkinson's is to always make it look good and look happy.

"It doesn't let you go with the reality of how difficult it can be sometimes."

On bad days, she may need help with everyday tasks, such as doing up the cuff buttons on a shirt or chopping vegetables.

Research ongoing

Looking into the future, Dr Lehn is hopeful about the possibility of new drugs that will slow the progression of the disease, while avoiding "harmful" talk of miracle cures.

"I want to give people realistic hope, not false hope," he said.

One research project he's working on is trying to change the gut bacteria in Parkinson's disease patients as a novel way of treating the condition.

Another study is investigating the use of "smart shoes" to assess the gait of patients living in regional and rural areas, so that exercise programs can be developed to reduce their risk of falls.

As research continues, Stacy and Jeremy Patterson are enjoying life as newlyweds.

They love to travel and are looking forward to a trip to Canada at the end of the year to celebrate Christmas in the snow.

"We love to cook," Dr Patterson said.

"We love to eat, probably a bit too much sometimes. And just spending time together, really."

April is Parkinson's Awareness Month.

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INFORMATION FOR

• Residents & Fellows
• Researchers

Second Annual Yale Parkinson's Disease Research and Clinical Care Symposium

The Second Annual Yale Parkinson's Disease Research and Clinical Care Symposium will take place on Monday, May 6, from 8:30 a.m. to 5 p.m. , at 100 College St., 11th floor, Room 1116. A cocktail hour and poster session will follow the symposium, from 5 to 6 p.m.

The event will feature an introduction to the Adams Center, the Parkinson and Movement Disorders Clinical Care Center, and the achievements of Yale's ASAP and Marcus Foundation grantees. The agenda for the day is as follows:

8:30-8:45 a.m. -- Welcome and Opening Remarks by Dean Nancy J. Brown, MD

8:45-9:45 a.m. -- How Can Genetics Lead to Cures? Moderator: Clemens Scherzer, MD, MBA

9:45-10:45 a.m. -- Is Parkinson's an Endo-Lysosomal Disease? Moderator: Pietro De Camilli, PhD

10:45-11 a.m. -- Break

11 a.m.-12 p.m. -- Why Are Synapses and Neuronal Circuits Important for Treating Parkinson's?

12-1:30 p.m. -- Lunch, Posters, and Networking

1:30-2:30 p.m. -- Can We Modulate the Immune System to Treat PD? Moderator: David Hafler, MD

2:30-3:30 p.m. -- Integrating Research and Patient Care, Moderator: Veronica Santini, MD

3:30-4 p.m. -- Break

4-5 p.m. -- Vision for the Future, Moderator: David Hafler, MD

5-6 p.m. -- Cocktail Hour/Hors D'oeuvres, More Posters, and Networking

See the full list of speakers for each of the panels.