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A Personalized Brain Pacemaker for Parkinson’s

In a new frontier for deep brain stimulation, researchers used A.I. to develop individualized algorithms, which helped a skateboarder and other patients with Parkinson’s disease.

By Pam Belluck

Photographs and Video by Jason Henry

Pam Belluck covers brain science and neurological disorders.

When Shawn Connolly was diagnosed with Parkinson’s disease nine years ago, he was a 39-year-old daredevil on a skateboard , flipping and leaping from walls, benches and dumpsters through the streets of San Francisco. He appeared in videos and magazines, and had sponsorships from skateboard makers and shops.

But gradually, he began to notice that “things weren’t really working right” with his body. He found that his right hand was cupping, and he began cradling his arm to hold it in place. His balance and alignment started to seem off.

Over time, he developed a common Parkinson’s pattern, fluctuating between periods of rapid involuntary movements like “I’ve got ants in my pants” and periods of calcified slowness when, he said, “I could barely move.”

A couple of years ago, Mr. Connolly volunteered for an experiment that summoned his daring and determination in a different way. He became a participant in a study exploring an innovative approach to deep brain stimulation.

In the study , which was published Monday in the journal Nature Medicine, researchers transformed deep brain stimulation — an established treatment for Parkinson’s — into a personalized therapy that tailored the amount of electrical stimulation to each patient’s individual symptoms.

The researchers found that for Mr. Connolly and the three other participants, the individualized approach, called adaptive deep brain stimulation, cut in half the time they experienced their most bothersome symptom.

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Tuesday, August 20, 2024

Self-adjusting brain pacemaker may help reduce Parkinson’s disease symptoms

Small NIH-funded trial shows the promise of personalized medicine.

A small feasibility study funded by the National Institutes of Health (NIH) found that an implanted device regulated by the body’s brain activity could provide continual and improved treatment for the symptoms of Parkinson’s disease (PD) in certain people with the disorder. This type of treatment, called adaptive deep brain stimulation (aDBS), is an improvement on a technique that has been used for PD and other brain disorders for many years. The study found aDBS was markedly more effective at controlling PD symptoms compared to conventional DBS treatments.

“This study marks a big step forward towards developing a DBS system that adapts to what the individual patient needs at a given time,” said Megan Frankowski, Ph.D., program director for NIH’s Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or The BRAIN Initiative ® , which helped fund this project. “By helping to control residual symptoms while not exacerbating others, adaptive DBS has the potential to improve the quality of life for some people living with Parkinson’s disease.”

DBS involves implanting fine wires called electrodes into the brain at specific locations. These wires then deliver electrical signals that can help mitigate the symptoms of brain disorders such as PD. Conventional DBS provides a constant level of stimulation and can also lead to unwanted side effects, because the brain does not always need the same strength of treatment. Therefore, aDBS uses data taken directly from a person’s brain and uses machine learning to adjust the level of stimulation in real time as the person’s needs change over time.

Four people already receiving conventional DBS were first asked what they felt was their most bothersome symptom that had persisted despite treatment. In many instances this was either involuntary movements or difficulty in initiating movement. The participants were then set up to receive aDBS treatment alongside their existing DBS therapy. After training the aDBS algorithm for several months, the participants were sent home, where the comparison test was performed by alternating between conventional and aDBS treatments. Changes occurred every two to seven days.

aDBS improved each participant’s most bothersome symptom roughly 50% compared to conventional DBS. Notably, even though they were not told which type of treatment they were receiving at any one time, three of the four participants were often able to correctly guess when they were on aDBS due to noticeable symptom improvement.

This project is a continuation of several years of work led by Philip Starr, M.D., Ph.D., and colleagues at the University of California, San Francisco. Previously, in 2018, they reported the development of an adaptive DBS system , referred to as a “closed loop” system, that adjusted based on feedback from the brain itself. Later, in 2021, they described their ability to record brain activity in people as they went about their daily lives.

Here, those two findings were combined to use brain activity recorded during normal life activities to drive the aDBS system. However, DBS treatment changed brain activity so much that the signal that had been expected to control the aDBS system was no longer detectable. This required researchers to take a computational and data-driven approach to identify a different signal within the brains of people with PD who were receiving conventional DBS therapy.

Conventional treatment for Parkinson’s disease often involves the drug levodopa, which is used to replace dopamine in the brain that has been lost because of the disorder. Because the amount of the drug in the brain fluctuates, peaking shortly after administration of the drug and gradually decreasing as it is metabolized by the body, aDBS could help smooth out the fluctuations by providing increased stimulation when drug levels are high and vice versa, making it an attractive option for patients requiring high doses of levodopa.

While these findings are promising, there remain significant challenges to overcome for this therapy to be more widely available. The initial setup of the device requires considerable input from highly trained clinicians. Researchers envision a future where most of the work would be managed by the device itself, greatly reducing the need for repeat visits to the clinic for fine tuning.

This type of automation is also necessary for other groups to test and eventually offer aDBS therapy in a clinical setting.

“One of the big issues facing DBS, even in approved indications like Parkinson’s, is access, both for patients in terms of where they can get it and also the physicians who need special training to program these devices,” said Frankowski. “If there were a way for a system to find the most optimal settings at the press of a button, that would really increase the availability of this treatment for more people.”

This study was supported by NINDS and NIH’s The BRAIN Initiative (NS10054, NS129627, NS080680, NS120037, NS131405, NS113637), Thiemann Foundation, and the TUYF Charitable Trust Fund. About the National Institute of Neurological Disorders and Stroke (NINDS):  NINDS is the nation’s leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

NIH’s The BRAIN Initiative , a multidisciplinary collaboration across  10 NIH Institutes and Centers , is uniquely positioned for cross-cutting discoveries in neuroscience to revolutionize our understanding of the human brain. By accelerating the development and application of innovative neurotechnologies, The BRAIN Initiative® is enabling researchers to understand the brain at unprecedented levels of detail in both health and disease, improving how we treat, prevent, and cure brain disorders. The BRAIN Initiative involves a multidisciplinary network of federal and non-federal partners whose missions and current research portfolios complement the goals of The BRAIN Initiative. 

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

NIH…Turning Discovery Into Health ®

Oehrn CR, Cernera S, Hammer LH, et al. “Chronic adaptive deep brain stimulation is superior to conventional stimulation in Parkinson’s disease: a blinded randomized feasibility trial.”  Nature Medicine  August 19, 2024. DOI:  10.1038/s41591-024-03196-z

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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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A Potential Parkinson’s Treatment Has Promising Results

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

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

The (potential) Parkinson's vaccine

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

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

The Parkinson's test

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

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

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

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

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

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

What the study found

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

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

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

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

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

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

Correction, June 26

Correction, June 25

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

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• Published: 19 April 2022

Redefining the hypotheses driving Parkinson’s diseases research

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

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

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

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Key genes and convergent pathogenic mechanisms in Parkinson disease

Introduction.

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

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

Multiple disease trajectories beneath the Parkinson’s disease umbrella

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Box 1 Glossary of terms.

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

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

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

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

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

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

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

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

Using big data to identify individual trajectories in a heterogeneous disease

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

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

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

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

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

Concluding remarks & future perspectives

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

Reporting Summary

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

Data availability

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

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Acknowledgements

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

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

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Parkinson's Drug Reduces Disease Markers in Breakthrough Trial

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Parkinson's Disease: Challenges, Progress, and Promise

Introduction.

Following Alzheimer’s disease, Parkinson's disease (PD) is the second-most common neurodegenerative disorder in the United States. Most people diagnosed with PD are age 60 years or older, however, an estimated 5 to 10 percent of people with PD are diagnosed before the age of 50. Approximately 500,000 Americans are diagnosed with PD, but given that many individuals go undiagnosed or are misdiagnosed the actual number is likely much higher. Some experts estimate that as many as 1 million Americans have PD. Of course, given the progressive nature of the disabilities associated with PD, the disease affects thousands more wives, husbands, children, and other caregivers.

In the United States alone, the cost of treating PD is estimated to be $14 billion annually. Indirect costs, such as those associated with the loss of productivity, are conservatively estimated to total $6.3 billion each year. As the U.S. population ages, these figures are expected to rise rapidly. The number of people diagnosed with PD in the United States is expected to double by 2040.

The National Institute of Neurological Disorders and Stroke ( NINDS ), part of the National Institutes of Health ( NIH ), has a long history of supporting PD research. For decades, NINDS-funded researchers working nationwide have developed treatment options that have greatly improved motor symptoms for people with PD. For example, dopamine replacement therapy with Sinemet, a mainstay therapy in the treatment of PD, has helped alleviate motor symptoms particularly in the early stages of disease. Deep brain stimulation (DBS) can reduce tremor, rigidity, stiffness, and improve movement. However, much work remains to be done. Despite their many successes, these therapies have limitations. There is no currently available therapy that slows the progression of the underlying disease or adequately relieves the wide range of symptoms in people with more advanced PD.

The NINDS brings scientists, health care providers, individuals with PD, caregivers, advocacy groups, and other stakeholders together to assess the state of PD research, define key challenges, and set priorities for advancing PD research. Most recently, the NINDS held the “Parkinson's Disease 2014: Advancing Research, Improving Lives” conference, which resulted in a series of prioritized recommendations that will inform ongoing and future efforts in PD research. This booklet highlights the recent progress made in PD research and maps out the challenges and priorities for the road ahead.

About Parkinson's

PD’s effects on the central nervous system are both chronic (meaning they persist) and progressive (meaning the symptoms grow worse over time). By the time a diagnosis is made, PD has typically already progressed to a point where people have difficulty controlling the movement of their bodies due to tremors (involuntary shaking), bradykinesia (slowness of movement and reflexes), stiffness in their limbs or the trunk of their body, and impaired balance. As these symptoms progress, walking, talking, swallowing, and completing other simple tasks can become challenging. 

In addition to these motor-related symptoms, non-motor symptoms such as cognitive impairment, mood and behavioral problems, sleep disorders, and constipation can significantly impair quality of life and require careful symptom-based treatment. Some non-motor symptoms such as hyposmia (reduced ability to detect odors), REM sleep-behavior disorder (acting out vivid dreams), and constipation typically precede the motor symptoms by several years. Other non-motor symptoms such as cognitive impairment commonly appear after the onset of motor symptoms. 

Many people with PD eventually develop dementia, but the time from the onset of movement symptoms to the onset of dementia symptoms varies greatly from person to person. Dementia is a leading reason for people with PD to transition from independent living at home to long-term care facilities.

PD disease processes begin well before people start exhibiting motor symptoms. This is the preclinical phase of the disease. During this phase people may experience a range of nonspecific, non-motor symptoms such as hyposmia, depression, anxiety, and sleep disorders. People may also experience disturbances of the autonomic nervous system that manifest as problems with digestion, respiration, salivation as well as excessive sweating, bladder dysfunction, or sexual dysfunction. This phase may last for several years. The onset of motor symptoms marks the clinical phase of PD. People may have a variety of symptoms including resting tremor, bradykinesia, rigidity (resistance to passive movement of the limbs), and balance problems. The progression of these symptoms is typically gradual, often involving only one side of the body at first. This includes things like a reduction of arm swing on one side when walking, soft speech, or intermittent tremor.

More research is needed to better understand, characterize, and identify features of the preclinical phase of PD. A high priority is placed on finding biological identifiers, or biomarkers, of these early phases so that people at high risk for progressing to the clinical phase of PD can be identified. In the future, therapeutics or other interventions may be available to prevent or slow the onset of the clinical phase of the disease among those at high risk for PD.

Currently available PD medications do offer valuable symptomatic relief, but as PD progresses, their use is often associated with significant and sometimes intolerable side effects. For example, levodopa, one of the most effective treatments for PD can normalize motor function for years but later cause involuntary muscle movements known as dyskinesia and dystonia (sustained muscle contractions). In addition, people in the mid to late stages of PD often experience a wearing-off of the beneficial effects of PD drugs and a re-emergence of motor and non-motor symptoms before their next scheduled dose. In more advanced PD, drug-resistant motor symptoms (e.g, postural instability, freezing of gait, loss of balance, frequent falls), behavioral changes (impulse control disorders, hallucinations, and psychosis), and often dementia are leading causes of impairment.

In addition to new therapeutic options, better diagnostic tools are needed to identify PD earlier in the course of the disease. By the time a person exhibits classic motor symptoms and is diagnosed with PD, substantial and widespread loss of brain cells and functions of the brain and autonomic nervous system have already occurred. Earlier diagnosis may provide a therapeutic window to slow or prevent the progression of PD prior to the onset of motor impairments.

Understanding the Pathology

The nervous system is made up of individual units called nerve cells or neurons. Neurons serve as a "communication network" within the brain and throughout a person’s body. Parkinson’s disease develops when neurons in the brain and elsewhere in the nervous system fail to function normally or die. The hallmark symptoms of PD — bradykinesia, tremor, postural instability, and rigidity — result primarily from the death of neurons in the substantia nigra, a region in the midbrain critical for motor control.

In order to communicate, neurons use chemical messengers called neurotransmitters. Neurotransmitters send information between neurons by crossing the space between them, called the synapse. Normally, neurons in the substantia nigra produce a neurotransmitter known as dopamine. Dopamine is critical for movement and it helps transmit messages within the brain to make sure muscles produce smooth, purposeful movement. Loss of dopamine results in abnormal nerve firing patterns that impair movement. By the time Parkinson’s is diagnosed, most people have lost an estimated 60 to 80 percent of their dopamine-producing cells in the substantia nigra.

While loss of dopamine accounts for the characteristic features of the disease, recent studies have revealed that a number of other brain systems are also damaged. These include the brain structures that regulate the chemical pathways that depend on norepinephrine, serotonin, and acetylcholine. The changes in these neurotransmitters and circuits may account for many of the non-motor features of PD.

A factor believed to play a fundamental role in the development of PD involves abnormalities of a protein called alpha-synuclein. In the normal brain, alpha-synuclein is located in nerve cells in specialized structures called presynaptic terminals. These terminals release neurotransmitters which carry signals between neurons. This signaling system is vital for normal brain function.

While normal alpha-synuclein functions are related to the storage and release of neurotransmitters, evidence suggests the buildup of excessive and abnormal alpha-synuclein plays a key role in the development of PD. There are rare examples of families in which certain genetic mutations in alpha-synuclein have been shown to cause the alpha-synuclein protein to misfold into an abnormal configuration. Most individuals with PD do not have a mutation in alpha-synuclein, but even when there is no mutation present, nearly every case of PD is associated with a buildup of abnormal and misfolded alpha-synuclein. As the misfolded protein accumulates, it clumps together into aggregates, or collections, that join together to form tiny protein threads called fibrils. Fibrils are the building blocks for Lewy bodies, abnormal structures that form inside nerve cells in the substantia nigra and elsewhere in the brain. Lewy bodies are a pathological hallmark of PD. Research suggests that the harmful buildup of alpha-synuclein may affect normal function and trigger nerve cell death.

Lewy bodies were discovered more than 100 years ago, and there are still unanswered questions about their role in disease. They are found in the brain of almost every patient affected by PD, but whether the Lewy bodies themselves contribute to the death of neurons is still unclear.  Alternatively, the accumulation of protein in Lewy bodies may be part of an unsuccessful attempt to protect the cell from the toxicity of aggregates of alpha-synuclein.

A key objective for researchers moving forward is to better understand the normal and abnormal functions of alpha-synuclein and its relationship to genetic mutations that impact PD.

Genetic Studies

In the past decade, NINDS-funded researchers have discovered much about the genetic factors that contribute to PD. In most instances the cause of PD is unknown, however, a small proportion of cases can be attributed to genetic factors. An estimated 15 to 25 percent of people with Parkinson’s disease have a family history of the disorder. It is relatively rare for PD to be caused by a single mutation of one of several specific genes. This only accounts for about 30 percent of cases in which there is a family history of PD and only 3 to 5 percent of sporadic cases — instances with no known family history.

Researchers increasingly believe that most, if not all, cases of PD probably involve both a genetic and environmental component. Early-onset Parkinson's disease is relatively rare and is more likely to be influenced by genetic factors than the forms of the disease that develop later in life.

Multiple NIH projects helped build an infrastructure for PD genetics research. The Human Genome Project and the International HapMap Project laid the groundwork for this research, producing tools to help researchers find genetic contributions to common diseases. Using these tools, researchers supported the Parkinson’s Disease Genome Wide Association Study (PD-GWAS). Funded by both the NINDS and the National Institute on Aging ( NIA ), this effort aims to detect genetic risk factors for PD from groups around the world. Included in PD-GWAS are data from nearly 14,000 people with PD and more than 95,000 people without PD. By comparing these two groups, researchers can identify patterns in certain regions, or loci, of the human genome where genes that cause or increase the risk of PD are likely to reside. Much like a zip code, genetic loci describe the general neighborhood of a gene.

Based on an analysis of PD-GWAS data and other sources, NIH-funded scientists have identified 28 loci believed to be independently associated with PD risk and many more loci have been tentatively linked to the disorder. 

Next generation genetic technologies have led to a number of new discoveries and allowed scientists learn more about what genetic factors contribute to the risk of developing PD. The first successes were a result of high-content genotyping, a method of identifying common variants in the human genome. Currently, there is a great deal of excitement regarding next generation sequencing — methods of genetic sequencing that allow for rapid sequencing of DNA base pairs in particular loci of the genome. These methods have significantly cut the time and costs required to identify genes involved with PD and will continue to facilitate the identification of PD-related genes in the future.

Another breakthrough in genetic sequencing is NeuroX, the first DNA chip able to identify genetic variants in a person’s genome to determine any risk for developing a number of late-onset neurodegenerative diseases, including PD. A joint venture between the NINDS and investigators at the NIA , the NeuroX chip was developed as a result of a 2011 NINDS workshop. The workshop led to an analysis of data from worldwide PD-GWAS investigations. Those studies helped correlate genetic variants and common traits among people with PD, which made the NeuroX chip possible.

Despite these innovations, significantly more research is needed to identify PD-related genes and the cellular processes they support in order to understand how these functions contribute to the onset and progression of PD. Common genetic variations alone cannot fully explain how genetics contributes to the risk of developing PD. Instead, researchers hypothesize there must be additional genetic contributions from variants that are not common enough to be detected by PD-GWAS investigations.

Known Genetic Mutations

Inherited PD has been found to be associated with mutations in a number of genes including  SNCA ,  LRRK2 ,  PARK2 , PARK7 , and  PINK1 . Many more genes may yet be identified. Genome-wide association studies have shown that common variants in these genes also play a role in changing the risk for sporadic cases.

Mutations in other types of genes, including  GBA , the gene in which a mutation causes Gaucher’s disease, do not cause PD, but appear to modify the risk of developing the condition in some families. There may also be variations in other genes that have not been identified that contribute to the risk of the disease.

• Gene for alpha-synuclein ( SNCA )

In 1997, scientists identified the first genetic mutation ( SNCA ) associated with PD among three unrelated families with several members affected with PD. The  SNCA  gene provides instructions for making the protein alpha-synuclein, which is normally found in the brain as well as other tissues in the body. Finding this mutation led to the discovery that alpha-synuclein aggregates were the primary component of the Lewy body. This is an example of how a disease-causing rare mutation can shed light on the entire disease process.

PD related to  SNCA  gene mutations is autosomal dominant, meaning that just one mutated copy of the gene in each cell is sufficient for a person to be affected. People with this mutation usually have a parent with the disease.

Though more than a dozen mutations in the  SNCA  gene have been linked to PD, these mutations are considered a relatively rare cause of the disease. In some cases,  SNCA  gene mutations are believed to cause the alpha-synuclein protein to misfold. Other  SNCA  mutations create extra copies of the gene, leading to excessive production of the alpha-synuclein protein. Even when no mutation is present, buildup of abnormal synuclein is a hallmark of PD. The NINDS is funding multiple studies aimed at determining how misfolded and excessive levels of alpha-synuclein might contribute to developing PD.

• Gene for leucine-rich repeat kinase 2 ( LRRK2 ) 

Mutations of the  LRRK2  gene are the most common genetic cause of autosomal dominant PD. These mutations play a role in about 10 percent of inherited forms of PD and about 4 percent of people who have no family history of the disease. Studies show that one particular  LRRK2  mutation, G2019S, accounts for up to 20 percent of PD in specific groups, such as the Ashkenazi Jewish population.

Researchers are still studying exactly how  LRRK2  gene mutations lead to PD, but it appears these mutations influence both the manufacturing and disposal of unwanted proteins in multiple ways. PD associated with  LRRK2  mutations involves both early- and late-onset forms of the disease. The  LRRK2  gene is a kinase enzyme, a type of protein that tags molecules within cells with chemicals called phosphate groups. This process of tagging, called phosphorylation, regulates protein enzymes by turning them “on” or “off” and it is fundamental to basic nerve cell function and health.

NINDS-supported investigators at the Udall Center at Johns Hopkins University (JHU) have found that  LRRK2  mutations increase the rate at which the gene’s protein tags ribosomal proteins, a key component of the protein-making machinery inside cells. This can cause the machinery to manufacture too many proteins, leading to cell death.

LRRK2  gene mutations also are believed to inhibit a waste disposal method called autophagy, the process by which cells breakdown nutrients, recycle cellular components, and get rid of unusable waste. Autophagy is a critical means for quality control by enabling the cell to eliminate damaged organelles and abnormal proteins.

LRRK2  gene mutations inhibit a type of autophagy called chaperone-mediated autophagy. During this type of autophagy a “chaperone” protein escorts a damaged protein to the lysosome, spherical vesicles within cells that contain acid that help breakdown unwanted molecules. As a result, the  LRRK2  gene mutations may lead to the buildup of alpha-synuclein into toxic aggregates within the cells. Researchers are exploring whether certain compounds might be capable of overriding  LRRK2  gene mutation effects by rebooting the chaperone-mediated disposal system.

• Gene for parkin ( PARK2 )/ Gene for PTEN induced putative kinase 1, or  PINK1  ( PARK6 )

PARK2  mutations are the most common genetic mutations associated with early-onset PD, which first appear at age 50 or younger.  PARK6  gene mutations also are associated with early-onset PD, but they are far more rare. Both types of mutations are associated with autosomal recessive PD, meaning that two mutated copies of the gene are present in each cell and that anyone affected may have unaffected parents who each carried a single copy of the mutated gene.

Findings from a NINDS-funded study suggest that people with  PARK2  mutations tend to have slower disease progression compared with those who do not carry  PARK2  mutations.

The genes  PARK2 ,  PARK6 ,  PINK1 , along with the protein parkin, are all involved at different points along a pathway that controls the integrity of mitochondria, the powerhouses inside cells that produce energy by regulating quality control processes. Brain cells are especially energetic and dependent upon mitochondrial energy supply. Specifically, parkin and PINK1  regulate mitochondrial autophagy — a process known as mitophagy. These processes are critical for maintaining a healthy pool of mitochondria by providing a means to eliminate those that no longer function properly.

Much work remains to be done to understand the association of  PARK2  and  PARK6  mutations and mitochondrial dysfunction, as well as to investigate if and how mitochondrial dysfunction leads to PD. Evidence suggests that parkin and  PINK1  function together. When  PINK1  (which is located on mitochondria) senses mitochondrial damage, it recruits parkin to get the process of mitophagy underway.

NINDS researchers are exploring ways to stimulate the  PINK1 /parkin pathway to encourage mitophagy. Scientists hope this will help them develop treatments for people with mitochondrial diseases, including certain forms of PD. Additionally, NINDS researchers are screening chemicals to identify agents that may be able to stimulate the expression of  PINK1 , and looking for other genes that may affect the functions of  PINK1  and parkin.

Evidence suggests that parkin is a factor in several additional pathways leading to PD, including sporadic forms of the disease associated with alpha-synuclein toxicity.

• Gene for DJ-1 ( PARK7 )

The  PARK7  gene encodes for the protein DJ-1. Several mutations in the gene for DJ-1 are associated with some rare, early-onset forms of PD. The function of the DJ-1 gene remains a mystery. However, one theory is it can help protect cells from oxidative stress. Oxidative stress occurs when unstable molecules called free radicals accumulate to levels that can damage or kill cells. Some studies suggest that the DJ-1 gene strengthens the cells’ ability to protect against metal toxicity and that this protective function is lost in some DJ-1 mutations. Animal studies suggest DJ-1 plays a role in motor function and helps protect cells against oxidative stress.  

• Gene for beta-glucocerebrosidase ( GBA )

Mutations in the gene encoding the lysosomal enzyme beta-glucocerebrosidase ( GBA ) are associated with a lysosomal storage disorder, Gaucher’s disease. People with Gaucher’s disease are also more likely to have parkinsonism, a group of nervous disorders with symptoms similar to Parkinson's disease. This has spurred investigators to look for a possible link between the two diseases. NIH-funded researchers have conducted studies of individuals with both disorders to assess their brain changes, family histories, and to screen tissues and DNA samples, which have helped confirm this link.

An NIH-led, multicenter study involving more than 10,000 people with and without PD showed that people with PD were more than 5 times more likely to carry a  GBA  mutation than those without the disease. Mutation carriers also were more likely to be diagnosed with PD earlier in their lives and to have a family history of the disease. Scientists have observed that depletion of beta-glucocerebrosidase results in alpha-synuclein accumulation and neurodegeneration.

Further research is needed to understand the association between  GBA  gene mutations and PD. The NINDS supports many lines of research investigating the role of  GBA  gene mutations. Projects are aimed at estimating the risk of PD associated with being a  GBA  carrier and identifying the phenotypic traits.

Studying the genes responsible for inherited cases of PD can help shed light on both inherited and sporadic cases of PD. The same genes and proteins that are altered in inherited cases of PD may play a role in sporadic cases of the disease. In some cases genetic mutations may not directly cause PD but may increase the susceptibility of developing the disease, especially when environmental toxins or other factors are present.

Cellular and Molecular Pathways to PD          

What happens in a person’s brain that causes him or her to develop PD? To answer this question scientists are working to understand the cellular and molecular pathways that lead to PD.

Mitochondrial Dysfunction

Research suggests that damage to mitochondria plays a major role in the development of PD. Mitochondria are unique parts of the cell that have their own DNA entirely separate from the genes found in the nucleus of every cell.

Mitochondrial dysfunction is a leading source of free radicals — molecules that damage membranes, proteins, DNA, and other parts of the cell. Oxidative stress is the main cause of damage by free radicals. Oxidative stress-related changes, including free radical damage to DNA, proteins, mitochondria, and fats has been detected in the brains of individuals with PD. A number of the genes found to cause PD disturb the process by which damaged mitochondria are disposed of in the neuron (mitophagy).

To learn more about how the process of mitophagy relates to PD, scientists have turned to RNA interference (RNAi), a natural process occurring in cells that helps regulate genes. Scientists are able to use RNAi as a tool to turn off genes of interest to investigate their function in cultured cells or animal models of PD. A technique known as high-throughput RNAi technology enabled NIH scientists to turn off nearly 22,000 genes one at a time. This process helped scientists identify dozens of genes that may regulate the clearance of damaged mitochondria. Researchers continue to study how these genes regulate the removal of damaged mitochondria from cells and the genes identified in this study may represent new therapeutic targets for PD.

One mechanism that helps regulate the health of mitochondria is autophagy, which allows for the breakdown and recycling of cellular components. Scientists have long observed that disruptions in the autophagy processes are associated with cell death in the substantia nigra and the accumulation of proteins in the brains of people with PD as well as other neurodegenerative diseases.

Ubiquitin-proteasome System

Another area of PD research focuses on the ubiquitin-proteasome system (UPS), which helps cells stay healthy by getting rid of abnormal proteins. A chemical called ubiquitin acts as a “tag” that marks certain proteins in the cell for degradation by proteasomes, structures inside cells that launch chemical reactions that break peptide bonds. Researchers believe that if this disposal symptom fails to work correctly, toxins and other substances may accumulate to harmful levels, leading to cell death. Impairment of the UPS is believed to play a key role in several neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases.

The contribution of UPS to the development of PD appears to be multifactorial, meaning UPS influences the interactions of several genes. NINDS-funded researchers have found that UPS is critical for the degradation of misfolded alpha-synuclein in cells. Conversely, evidence suggests that abnormal or misfolded alpha-synuclein may also inhibit the proper functioning of UPS. A feedback loop may exist whereby abnormal alpha-synuclein inhibits the functions of UPS, causing more abnormal alpha-synuclein to accumulate and additional suppression of UPS activity. NINDS-funded researchers have also identified proteins that accumulate in the absence of parkin that contribute to the loss of dopaminergic neurons.

Several NINDS-funded investigators are exploring ways of enhancing UPS function as a potential therapeutic strategy.

Cell-to-cell Transmission of Abnormally-folded Proteins

Researchers have learned more about how PD-related damage spreads to various parts of the brain and nervous system. A characteristic pattern has emerged by which Lewy bodies are distributed in various regions of the brain. The earliest brain changes appear to involve Lewy bodies in the brain stem region (medulla oblongata and pontine tegmentum, as well as the olfactory bulb).

Braak staging is a six-tier classification method used to identify the degree of postmortem pathology resulting from PD. According to this classification, people in Braak stages 1 and 2 are generally thought to be presymptomatic. As the disease advances to Braak stages 3 and 4, Lewy bodies spread to the substantia nigra, areas of the midbrain, the basal forebrain, and the neocortex.

More recent evidence suggests that even before such brain changes have occurred, alpha-synuclein aggregates and Lewy bodies can be found in the nervous system of the gastrointestinal tract and in the salivary glands, a finding that supports the theory that PD many originate not in the brain but in the autonomic nervous system. Non-motor symptoms such as constipation may in fact be a sign of the disease affecting nerves outside the brain before the disease moves into the brain where it later affects regions that control movement.

Researchers at the Udall Center at the Perelman School of Medicine of the University of Pennsylvania injected mice with a synthetic form of abnormal alpha-synuclein and found that misfolded alpha-synuclein appeared to spread throughout the brain. The researchers hypothesize that the injected abnormal alpha-synuclein may act like a seed that triggers the mouse’s own alpha-synuclein to misfold, leading to a cell-to-cell transmission of PD-like brain changes, especially in regions of the brain important for motor function. The mice also exhibited PD-like motor symptoms.  

Understanding more about how abnormal proteins spread through the nervous system may provide a potential window for a therapeutic strategy that interrupts the process of protein transmission and slows or halts disease progression. For example, NINDS-funded investigators are looking at immune therapy and antibodies or immunization against alpha-synuclein, to block PD transmission in the brains of mice.

Environmental Influences Environmental circumstances are thought to impact the development of PD. Exposure to certain toxins may have a direct link to the development of PD. This was the case among people exposed to MPTP, a by-product accidentally produced in the manufacture of a synthetic opioid with effects similar to morphine. During the 1980s, street drugs contaminated with this substance caused a syndrome similar to PD. MPTP is also structurally similar to some pesticides. The brain converts MPTP into MPP+, which is toxic to substantia nigra neurons. MPP+ exposure produces severe, permanent parkinsonism and has been used to create animal models of PD. 

In other cases, exposure to the metal manganese among those with working in the mining, welding, and steel industries has been associated with an increased risk of developing parkinsonism. Some evidence suggests that exposure to certain herbicides such as paraquat and maneb increase the risk of PD. Scientists believe that there are other yet-to-be identified environmental factors that play a role in PD among people who are already genetically susceptible to developing the disease.

The National Institute of Environmental Health Sciences ( NIEHS ) is the lead institute at the NIH investigating the association between PD and environmental influences such as pesticides and solvents as well as other factors like traumatic brain injury. For example, NIEHS is funding a project at the University of Washington aimed at developing and validating biomarkers to identify early-stage neurological disease processes associated with toxic agents such as chemicals, metals, and pesticides. Animal models are being developed to study the impact of pesticides on farmworkers and metals on professional welders.

The NIEHS also funds the Parkinson’s, Genes & Environment study. The study is designed to determine the role genes as well dietary, lifestyle, and environmental factors play on the risk for developing PD and their potential to cause the illness. The more than 500,000 study participants were originally recruited in 1995 as part of the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study. Researchers will continue to follow participants over time to address some of the most interesting theories about the causes of PD. Already they have found, for example, that people who consume low levels of healthy dietary fats, such as those from fish, or high levels of saturated fats are more vulnerable to developing PD after being exposed to neurotoxins such as pesticides. The findings need to be confirmed, however, they suggest the possibility that diets rich in healthy fats and low in saturated fats may reduce the risk of PD.

The development of PD is a complex interplay between environmental, genetic, and lifestyle factors. Scientists are increasingly aware that in any given individual, there may be multiple factors that cause the disease.

In some cases, environmental factors may also have a protective effect. Population-based studies have suggested, for example, that people with high levels of vitamin D in their blood have a much lower risk of developing PD compared with people with very low concentrations of vitamin D. Further research is need to determine if vitamin D deficiency puts people at higher risk for PD, but such findings suggest the possibility that vitamin D supplements may have a beneficial effect. However, there may be genetic factors that cause people with low vitamin D levels to have higher rates of PD in which case vitamin D supplements would not be helpful.

To answer to this question, researchers at the Udall Center at the University of Miami are examining the pharmacogenetics of vitamin D. The investigators are studying a large dataset to confirm the finding that low levels of vitamin D is a risk factor for PD. At the same time, they are trying to identify any potential genetic modifiers of vitamin D’s effect on PD risk.

Certain drugs and chemicals available as a supplement or in a person’s diet also have been shown to have a neuroprotective effect for PD and other disorders. For example, regular use of caffeine (coffee, tea) was found to reduce the loss of dopamine-producing neurons. Studies hope to define the optimal caffeine dose in treating movement disorders like PD while gaining a better understanding of the mechanisms involving caffeine’s benefit. Uric acid, because of its antioxidative effect, may lower the risk for multiple neurodegenerative disorders, in particular, PD. A preliminary clinical trial funded by the Michael J. Fox Foundation examined the effectiveness of the drug inosine to safely raise uric acid levels and possibly slow the progression of Parkinson’s disease.

Neuroinflammation Neuroinflammation is a protective biological response designed to eliminate damaged cells and other harmful agents in nervous system tissue. Mounting evidence suggests that neuroinflammation plays a role in PD. Several lines of research funded by the NINDS are investigating this connection.

Compared to people without PD, those with PD tend to have higher levels of pro-inflammatory substances known as cytokines in their cerebrospinal fluid. Immune cells in the brain called microglia also are more likely to be activated in the brains of individuals with PD. Epidemiological studies suggest that rates of PD among people who frequently use non-steroidal anti-inflammatory drugs (NSAIDS) are lower than in those who do not use NSAIDS.

Evidence from animal studies also suggests that elevated levels of the protein alpha-synuclein may trigger microglia to become activated in the brains of people with PD.  

Currently, scientists are investigating whether inflammation itself is a cause of brain cell death or if it is a response to an already occurring process that contributes to the development of a disease. If researchers can interrupt the neuroinflammatory processes, they may be able to develop neuroprotective treatments for people with PD that prevent or slow the progression of the disease by halting, or at least reducing, the loss of neurons.

Models for Studying PD Much of the research advancing our understanding and treatment of PD would not be possible without research models — yeast, fruit flies, worms, fish, rodents, and non-human primates  — that have specific characteristics that mimic PD biology in humans. Scientists depend on these models to investigate questions about what goes wrong in PD, how cellular processes fit into the context of neuronal circuits, and how potential new treatments affect these disease processes.

The NINDS supports ongoing studies at the Udall Centers and elsewhere to refine existing research models and develop new ones. Better models are needed to more accurately mimic human disease in animals and to study PD’s mechanisms and potential treatments. Currently, none of the models express all the key pathologic features of PD or reflect the complement of clinical motor and non-motor features of the disease in humans.

In addition to creating new animal models, NINDS-funded researchers also look for ways of combining different types of models (i.e., genetic and toxin-induced) to better understand the interplay between genetic and environmental factors that contribute to the development of PD. 

Genetic Models The identification of genetic mutations among some families with hereditary forms of PD led to the development of animal models (rodent, non-human primate, worm, and fly) engineered to have mutations or deletions of PD genes. Each model has its strengths and shortcomings in helping researchers study the disease.

For example, mice with  SNCA  mutations develop an adult-onset degenerative disease characterized by movement dysfunction and aggregation of alpha-synuclein, but these mice have no loss of dopaminergic neurons. Other mice have been engineered to express  LRRK2  mutations, but show little evidence of PD symptoms. Fruit flies and worms engineered to overexpress  LRRK2  exhibit reductions in motor abilities and loss of dopamine neurons, but they do not adequately reflect the disease as it occurs in humans.

Scientists have developed numerous models aimed at interrupting key cellular functions known to play a role in PD. For example, the MitoPark mouse model disrupts the functioning of the mitochondria, leading to some PD-like motor symptoms that respond to levodopa treatment.

Toxin-induced Models For decades, the most widely used models for studying PD involved those in which toxins were used to induce PD-like motor symptoms. Such models were used to evaluate potential therapies. The first toxin-induced models relied on MPTP or the neurotoxin 6-hydroxydopamine to kill dopamine-producing neurons in the substantia nigra, causing PD-like motor symptoms. Later, researchers developed another type of model that examined how toxins interfered with the activities of mitochondria. Toxins for this purpose included the pesticide rotenone and the herbicides paraquat and maneb. Rats exposed to such toxins develop large inclusions in substantia nigra neurons that resemble Lewy bodies and contain alpha-synuclein and ubiquitin. The animals also developed bradykinesia, rigidity, and gait problems. Such toxin models are helpful for studying the consequences of dopamine depletion. However, they are limited in their ability to model the all the factors that cause PD in humans.

Induced Pluripotent Stem Cells Genetic engineering is another mechanism for modeling some of the processes that go wrong in PD. Recently scientists developed a breakthrough modeling mechanism using induced pluripotent stem cells (iPSCs), which are cells that can become any type of cell in the body. Researchers take samples of skin, blood, hair follicles, or other types of tissue from a person with PD and then manipulate those cells to become iPSCs. These cells are then programmed to become dopaminergic neurons, making it possible for scientists to study the molecular and cellular mechanisms that lead to PD as well as potential treatments. NIH-funded researchers have also coaxed iPSCs to become tissue from other parts of the body such as the gastrointestinal tract and the heart, allowing them to study the mechanisms of PD in other regions of the body.

NINDS-funded researchers at the Udall Center at Johns Hopkins University have used iPSCs from people with PD as well as presymptomatic people who carry  PARK6  or  LRRK2  genetic mutations to develop brain cells to study specific aspects of mitochondrial functioning. They also are testing potential ways of intervening to reverse mitochondrial dysfunction.

The ability to create neurons or other cell types from an individual with PD presents the possibility of providing a personalized treatment approach. iPSC-derived neurons may prove useful for testing the effectiveness of a drug before giving it to people with PD. 

The NINDS created and supports an open-access repository of iPSCs from people who have genetic mutations associated with PD. Specimens in the repository are collected and characterized by a team of collaborating researchers at seven major institutions participating in the Parkinson’s iPSC Consortium. The iPSCs are available through the NINDS Repository for researchers to study the causes of PD, as well as to screen potential drug therapies.

Improving Diagnosis

There is no single definitive test for diagnosing PD in a living person and there is no way to track disease progression on a biological level. Aside from finding a cure, the holy grail of PD research is the discovery of biomarkers — detectable and measurable changes in the body that can be used to predict, diagnose, and monitor disease activity and progression. Biomarkers can be identified through a number of different methods, including imaging scans (e.g., MRI, CT), biological samples (e.g., cerebrospinal fluid, plasma), and genetic studies. The risk for heart disease, for example, can be detected by measuring cholesterol or blood pressure. People at risk for PD currently lack a similar means for risk detection.

The ideal PD biomarker would be one that can be easily tested, varies with disease severity, and is abnormal during the preclinical phase of the illness before a person has any symptoms. Reliable biomarkers would allow physicians to screen and identify people at increased risk of developing PD and more accurately monitor disease progression among people who have been diagnosed with the disease.  

Biomarkers would also greatly accelerate clinical research efforts by shortening the timeframe needed to show that a drug has successfully engaged a disease-specific target in the brain or nervous system. Such measures may be available long before meaningful clinical changes are evident after a person has tried a particular therapy or intervention. Biomarkers may also be useful for determining optimal drug dosage.

Progress toward the development of biomarkers is occurring on several fronts.

The U.S. Food and Drug Administration (FDA) has approved the use of brain imaging technology to detect dopamine transporters (DaT), an indicator of dopamine neurons, to help evaluate adults with suspected parkinsonism. The DaTscan uses an iodine-based radioactive chemical along with single-photon emission computed tomography (SPECT, imaging involving blood flow to tissue) to determine whether there has been a loss of dopamine-producing neurons in a person’s brain. However, DaTscan cannot diagnose PD, nor can it accurately distinguish PD from other disorders that involve a loss of dopamine neurons.

NINDS scientists are trying to develop additional ways of imaging the brain and measuring neurochemicals in order to look for early signs of PD. In one study, researchers are comparing brain images from people with PD with images from people who might have early symptoms of PD, as well as people without signs of PD. The objective is to provide a picture of how PD affects the brain over time.

Given the critical contribution that alpha-synuclein is believed to play in the development of PD, a high-priority goal is to develop a positron emission tomography (PET) imaging agent that can show alpha-synuclein accumulation in the brain. Currently, alpha-synuclein levels and localization in the brain can only be confirmed by an autopsy. The ability to detect the protein with an imaging technology in a living person would enable physicians to track the severity of alpha-synuclein accumulation over time, as well as to provide a means to gauge the success or failure of therapies aimed at reducing alpha-synuclein levels. Such a tool would be a game changer for accelerating drug development.

PET imaging produces a three-dimensional image of functional processes in the body. The technique requires the injection of a radiotracer agent to target the alpha-synuclein protein so that it can be visualized. Several NINDS-funded researchers and a consortium of researchers assembled by the Michael J. Fox Foundation are working to develop such an alpha-synuclein radiotracer.

NINDS researchers are conducting a longitudinal study of a large population of people — half of whom have multiple risk factors for PD while the other half have no obvious risk factors — as a way of identifying and validating biomarkers for predicting the development of PD. Many of the biomarkers being tested measure functioning of the autonomic nervous system because, as research suggests, non-motor symptoms associated with the autonomic nervous system often precede motor symptoms.

Advancing Treatments

A personalized medicine approach that treats an individual with PD in a timely manner with the optimal treatment requires understanding the enormously complex and diverse set of factors that contribute to PD. The disease processes that lead to PD involve numerous potential variables and pathways operating at cellular and molecular levels. Most of these processes unfold over the course of many years and begin well before individuals start having symptoms. People with PD may also differ significantly in terms of the symptoms they experience, the severity of those symptoms, disease progression, and their response to treatment and risk of complications.

Improving our understanding of what causes the complexity and diversity of PD is a major challenge for researchers. Tools are needed to group people with similar types of PD so that individuals who are most likely to benefit from clinical trials can be studied and their responses to treatment can be compared in a meaningful way.

Neuroprotection and Disease Modification

A current NINDS study is focused on a potentially neuroprotective treatment that modulates calcium levels for newly-diagnosed individuals with PD. Cells in the body, including dopamine neurons in the brain, maintain optimal levels of calcium by pumping it in and out of their membranes through pore-like openings called channels. When calcium levels are too low, cells do not function properly. If they are too high, cells die. Scientists have long observed that imbalances in calcium may play a role in the development of PD.

Recent research also suggests that modifying the effects of calcium with calcium channel blockers — some of which are already on the market for treating high blood pressure — may potentially slow the progression of PD. Some population studies report that people who take calcium channel-blocking medications have decreased risk of PD. Using a mouse model of PD, researchers at the Northwestern Udall Center have shown that the calcium channel blocker isradipine can protect dopamine neurons from a variety of toxins. A preliminary study of isradipine in people with PD demonstrated relative safety. Researchers hope to confirm results in a larger, ongoing multicenter trial that is currently recruiting early-stage PD patients. Other NINDS-funded researchers continue to screen additional calcium channel blocking agents in order to develop potential neuroprotective treatments for people with PD.

In people with sporadic forms of PD, evidence suggests that parkin, normally neuroprotective, becomes inactive, pointing to a possible link between parkin and sporadic PD. NINDS-funded researchers have discovered ways of modifying the parkin protein to boost its neuroprotective activity.  Since PD is caused by the death of dopamine-producing neurons, a trial of embryonic cell replacement was attempted but did not demonstrate benefit. As researchers learn more about induced pluripotent stem cells they may be able to create healthy dopamine cells that can be transplanted into the brain as a form of therapy. 

Animal models and clinical studies suggest that the body’s immune system may contribute to the pathology of Parkinson's disease. NINDS-supported researchers are looking at whether a drug called sargramostim, which is a synthetic version of a substance that helps bone marrow manufacture new white blood cells to fight infection, can be used to restore immune system functions.

Gene Therapy

Glial cell derived neurotrophic factor (GDNF) is a protein that may help protect and strengthen brain cells that produce dopamine. Researchers are testing the ability of these cells to deliver GDNF to key areas of the brain with the help of a viral vector known as adeno-associated virus (AAV). Using a brain infusion technique, researchers deliver AAVs that have been programmed to produce GDNF into a person’s brain. The therapeutic approach is being tested among people with advanced PD.

Deep Brain Stimulation

The U.S. Food and Drug Administration first approved deep brain stimulation (DBS) for the treatment of PD-related tremor in 1997. The NINDS supported pioneering research contributing to the development of DBS, which has become widely used and is one of the most effective options for treating PD once levodopa treatment becomes problematic. Much of the research that led to the development of DBS was performed by NINDS-funded scientist Dr. Mahlon DeLong and his colleagues, who have been instrumental in defining the complex circuits in the brain that malfunction in PD. Ongoing NINDS funded research is currently building upon this scientific foundation to understand the therapeutic mechanisms and long-term effects of circuit-based treatment of PD by DBS.

DBS involves the implantation of electrodes into deep parts of the brain, typically the subthalamic nucleus or the globus pallidus. A pulse generator is also implanted under the individual’s collarbone to send finely controlled electrical signals to the DBS electrodes through wires placed under the skin. When turned on externally, the pulse generator and electrodes stimulate the brain to block signals that cause many of the motor symptoms of PD. How DBS helps control the symptoms of PD is not well understood.

In a study conducted by the NINDS and the Department of Veterans Affairs, bilateral DBS was found to more successfully control PD motor function symptoms and improve quality of life than even the most effective medications. DBS provides symptom relief for many people with PD, but it does not work for everyone. PD symptoms persist in some people despite DBS treatment. Researchers continue to look for ways of improving DBS so that it benefits a greater number of people.

For example, NINDS-supported researchers are attempting to deliver a more highly targeted stimulation of specific regions of the brain—the globus pallidus interna (GPi) and the subthalamic nucleus (STN) — to see if it makes a difference in terms of the duration of motor improvements. Other researchers are studying the effects of combining STN DBS with stimulation of the pedunculopontine nucleus (PPN, located in the brain stem) to improve gait control in people who continue to have difficulty walking and talking following STN DBS alone.

NINDS-funded researchers are also investigating different forms of brain stimulation that may be less invasive than DBS. Transcranial direct current stimulation (tDCS) involves attaching electrodes to the skin, or just beneath it, to deliver low doses of electrical current to the brain. Researchers, with support and funding from the NINDS , have also developed ParkinStim, a device that people with PD wear while sleeping. People with PD often feel worst in the morning because the medication they took the night before has worn off. Stimulation during the night may help these individuals wake up feeling better. While tDCS may not replace DBS, it may allow people to delay starting DBS therapy. It may also help individuals with PD decrease the amount or frequency of their medication. 

Other NINDS-funded investigators aim to improve DBS success by understanding how DBS works. For example, NINDS-funded researchers developed a device known as WINCS (wireless instantaneous neurotransmitter concentration sensor system) that measures the release of chemicals or neurotransmitters in the brain. The WINCS device is being used in conjunction with functional MRI (fMRI) to look at brain activity and neurotransmitter release during DBS. Such information may be used to design closed-loop controllers capable of monitoring neurochemical activity so that DBS stimulation can be adjusted accordingly.

Taken together, these advances in understanding, tools, and techniques may begin to point to entirely new ways of modulating the brain’s circuits that will benefit people with treatment-resistant PD. For example, researchers at the Udall Center at Emory University are using animal model systems to understand the effects of DBS and other neurosurgical interventions on brain network elements downstream from the basal ganglia, the part of the brain responsible for voluntary motor function. These studies will not only allow researchers to better understand how DBS works but also to improve treatment and care for people with PD.

Drug-Induced, Treatment-resistant, Non-motor symptoms A major objective of PD research is to develop treatments for symptoms that do not respond to currently available medications or DBS. Therapies are still lacking for motor symptoms such as freezing of gait and non-motor symptoms such as cognitive impairment, dementia, sleep disorders, and symptoms involving the autonomic nervous system. The NINDS supports many studies that address these features.

• Levodopa-induced dyskinesias.  Early on, Parkinson’s disease can generally be effectively managed for many years with dopaminergic treatments using a drug known as levodopa. However, the majority of people using this drug eventually develop levodopa-induced dyskinesias (e.g., tics, tremors). Based on the results from animal studies, one hypothesis is that levodopa may be associated with neurovascular changes that alter the ability of the drug to pass through the blood-brain barrier.

The Udall Center at the Feinstein Institute for Medical Research is leading investigations into strategies for preventing drug-induced symptoms, which are such an important quality of life issue for many people with PD. Using advanced PET imaging, Feinstein researchers are examining blood flow dynamics among people with and without levodopa-induced dyskinesias. Using an animal model, the researchers hope to determine whether changes in blood flow are associated with structural changes in the tiny blood vessels surrounding the brain or with the permeability of the blood-brain barrier.

• Dementia.  NINDS-supported researchers are conducting several clinical trials aimed at gaining a better understanding PD-related dementia, which affects a substantial portion of people with PD and for which there are virtually no treatments. Among the many lines of research addressing PD-related dementia, one longitudinal study is following people with PD and healthy volunteers over time. Participants take thinking and memory tests as researchers measure their brain activity using imaging studies, among other tests. Researchers also analyze participant’s brain tissue after they die. Investigators hope that these studies will provide information on the pathology occurring in regions of the brain that are affected in people who have PD-related dementia.

Several Udall Centers, including the Pacific Northwest Udall Center (PANUC) and the Penn Udall Center also have projects devoted to PD-related dementia and cognitive impairment. In a study of more than 600 people with PD, PANUC researchers found that at baseline nearly 60 percent had mild cognitive impairment and 22 percent had dementia. Men were more likely to have cognitive impairment than women.

• Disruption of sleep . Excessive daytime sleepiness and an inability to sleep throughout the night are some of the most common and most disabling non-motor symptoms of PD. Mechanisms leading to impaired sleep are not well understood and treatment options are limited. NINDS-supported researchers are examining markers of the circadian system — which controls the body's "biological clock" — sleepiness, and sleep quality in people with PD and healthy controls. They are also looking at the effects of bright light exposure to see if it has an effect on circadian rhythms and sleepiness.
• Freezing of gait.  This condition is a common and disabling symptom of PD, often leading to significant declines in quality of life. Walking requires shifting from one leg to the other. A person suffering from freezing of gait experiences a sense of falling every time he or she lifts a foot up off the floor. Every step forward resembles a controlled fall. Research has shown that auditory stimuli (sounds of a metronome) or visual cues (a flash of light or lines on the floor indicating stride length) can reduce episodes of freezing, but how these cues work is a mystery. NINDS-supported researchers are trying to determine the best way to treat freezing of gait. For example, researchers at the Udall Center for Excellence at the University of Michigan are using innovative Positron emission tomography (PET) imaging techniques to examine the mechanisms involved with gait, postural control, and attentional function.
• Neurogenic orthostatic hypotension.  The autonomic nervous system controls blood pressure. People with diseases that disrupt the autonomic nervous system, such as PD, are therefore at risk of sudden drops in blood pressure that can lead to fainting. Research funded by the NINDS led the FDA to approve the use of Northera capsules (droxidopa) for the treatment of neurogenic orthostatic hypotension in 2014.

Living Well with Parkinson's

While medication and DBS surgery are the most effective treatments for PD, individuals often choose to delay these treatments because of their adverse side effects. Until a therapy is developed that can halt the progression of PD, there is a significant need for strategies that provide symptom relief without causing negative side effects.

Diet, Exercise, and Stress Reduction

Findings from several studies suggest that exercise has the potential to provide relief from certain PD symptoms. Anecdotally, people with Parkinson’s disease who exercise typically do better. However, many questions remain. Among them is whether exercise provides a conditioning effect by strengthening muscles and improving flexibility or whether it has a direct effect on the brain.  

In an NINDS-funded trial comparing the benefits of tai chi, resistance training, and stretching, tai chi was found to reduce balance impairments in people with mild-to-moderate PD. People in the tai chi group also experienced significantly fewer falls and greater improvements in their functional capacity.

The NINDS funds many studies aimed at determining how exercise benefits PD and identifying exercise regimens that improve PD symptoms. An important question is whether exercise provides people with newly-diagnosed PD a means for delaying treatment with drug therapy or DBS. NINDS-supported researchers are comparing the effects of moderate and vigorous exercise regimens with no exercise (control group) in a clinical trial to see if it can help slow the progression of symptoms.

Another study is using neuroimaging techniques to compare the neurophysiologic effects of tango dancing, treadmill training, and stretching (control group) on brain function and connectivity. The results may help explain how exercise influences function in PD and help identify which brain regions are involved. The hope is that these findings will lead to better treatments for gait difficulties by identifying specific exercise interventions and targets for DBS.

Technologies that Improve Quality of Life

New technologies may provide measurable quality of life improvements among people with PD. For example, wearable “smart home” devices may present a far more accurate and nuanced picture of an individual’s symptom status compared to a typical physical exam performed in a physician’s office. NINDS has funded a technology laboratory at the University of Rochester to develop and test technologies for PD research and the care of patients. Scientists there have worked with Apple to develop smartphone apps to assess PD symptoms. NINDS researchers are testing the feasibility of using a portable computer module, called a quantitative motor assessment tool (QMAT), to collect information about a person’s disease impairment — all without requiring a trip to a medical center.

The NINDS also supports the development of adaptive technologies that enable people with neurological disorders to independently perform daily activities. The NINDS funding led to the development of the Liftware spoon, a chargeable electronic spoon that uses a microchip and sensors to detect the direction and force of a tremor before motoring the spoon in the opposite direction to cancel out the movement and make it easier to eat. Studies show that the spoon reduces the disruption of tremor by 70 percent.

Research using brain tissue, donated after death, is critical to advancing the understanding of Parkinson’s disease and other neurodegenerative diseases. However, this precious resource is in short supply. New approaches to brain banking are necessary and better communication is needed with all stakeholders, including people with neurodegenerative diseases and their families. The NINDS supports several projects aimed securing resources for research.

• The NIH NeuroBioBank ( https://neurobiobank.nih.gov ) is a network of brain and tissue repositories throughout the United States that coordinates the collection, evaluation, processing, storage, and distribution of nervous system tissue and associated clinical data. The project, funded by the NINDS, the National Institute of Mental Health, and the  Eunice Kennedy Shriver  National Institute of Child Health and Human Development brings together researchers, NIH program staff, information technology experts, disease advocacy groups, and individuals seeking information about opportunities to donate. Repositories in the network are dedicated to collecting specimens in a standardized and transparent way so they can be made available for use by the broader research community. The repositories are linked through a common informatics platform, providing researchers with easy access to a centralized resource housing thousands of biospecimens from donors with a variety of diseases of the nervous system.
• The National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders at the Banner Sun Health Research Institute in Sun City, Arizona, conducts ongoing clinical assessments of  healthy elderly individuals and people with PD and related disorders who are willing to donate their brain and other biospecimens for research purposes. Participants are autopsied when they die and biospecimens are stored and available to the broader research community.
• The NINDS Human Genetics DNA and Cell Line Repository at the Coriell Institute ( https://catalog.coriell.org/1/NINDS ) provides researchers with resources for studying genetic causes of nervous system disorders. The bank includes a variety of samples including iPSCs from participants with Parkinson’s disease as well as other forms of parkinsonism. Also included in the collection are samples from participant’s family members and normal healthy controls.

PD research has progressed enormously in recent years. Scientists are rapidly working to unlock the mysteries of Parkinson’s, and treatments that restore lost function, halt disease progression, and prevent the condition are now realistic goals. Many of these advances are the result of discoveries from NINDS-funded basic, translational, and clinical investigators across the United States as well as NINDS-supported research at the Udall Parkinson’s Disease Research Centers of Excellence. Studies funded by the NIH have identified several genetic mutations that make individuals susceptible to Parkinson’s disease and breakthroughs in genetic research make finding new genetic factors easier and more efficient. A number of promising new therapies have been developed and are currently being tested in animals as well as people. As scientists work to learn more about the underlying biology of the disease and the complex interplay between genetic and environmental influences, new biomarkers will be discovered, therapies for relieving PD symptoms will continue to improve, and ultimately the disease may be halted, reversed, or even prevented from occurring at all.

Sidebar: Morris K. Udall Centers of Excellence for Parkinson's Disease Research

The Morris K. Udall Parkinson’s Disease Research Act of 1997 authorized the NIH to greatly accelerate and expand PD research efforts by launching the NINDS Udall Centers of Excellence, a network of research centers that provide a collaborative, interdisciplinary framework for PD research. Udall Center investigators, along with many other researchers funded by the NIH, have made substantial progress in understanding PD, including identifying disease-associated genes; investigating the neurobiological mechanisms that contribute to PD, developing and improving PD research models, and discovering and testing potential therapeutic targets for developing novel treatment strategies.

The Udall Centers continue to conduct critical basic, translational, and clinical research on PD including: 1) identifying and characterizing candidate and disease-associated genes, 2) examining neurobiological mechanisms underlying the disease, and 3) developing and testing potential therapies. As part of the program, Udall Center investigators work with local communities of patients and caregivers to identify the challenges of living with PD and to translate scientific discoveries into patient care. The Centers also train the next generation of physicians and scientists who will advance our knowledge of and treatments for PD.  See the full list of Udall Centers .

Sidebar: NINDS Steps Up Pursuit of PD Biomarkers

In 2012, the NINDS dramatically accelerated efforts to identify biomarkers by establishing the Parkinson’s Disease Biomarkers Program (PDBP). This unprecedented program unites a range of stakeholders from basic and clinical researchers to healthcare professionals, the NINDS staff, information technology experts, and people living with PD and their families.

PDBP supports research and builds resources aimed at accelerating the discovery of biomarkers to ultimately slow the progression of PD. For example, the program has established a repository of biological specimens and a Data Management Resource (DMR) system maintained by the NIH Center for Information Technology. The DMR allows researchers to access clinical, imaging, genetic, and biologic data, while a complementary PDBP-supported project develops statistical tools to analyze vast quantities of data so that patterns can be identified across these diverse sources of information.

PDBP supports several new and existing clinical studies that collect and analyze biospecimens such as blood, urine, and cerebrospinal fluid from people with all stages of PD as well as those without the disease. Several lines of research are looking at various proteins in these biospecimens to explore their value as markers of PD and its progression. Biospecimens are analyzed along with detailed clinical information on signs and symptoms such as gait, balance, sleep problems, memory deficits, and hyposmia. Imaging techniques are used at different stages of disease to analyze brain function in areas associated with movement and cognition.

Once a potential biomarker is identified, the next step is to validate it to make sure that it consistently and reliably provides meaningful information about PD. The PDBP studies complement work being done through the Michael J. Fox Foundation’s biomarker project and the Parkinson’s Progression Markers Initiative (PPMI), which seeks to validate biomarkers. The NINDS also works with the Michael J. Fox Foundation on BioFIND, a two-year observational clinical study in which investigators collect blood and cerebrospinal fluid from people with and without PD. The samples can be used in multiple research projects designed to discover and verify biomarkers of PD.

Sidebar: Advances in Circuitry Research

The brain contains numerous connections among neurons known as neural circuits.

Research on such connections and networks within the brain have advanced rapidly in the past few years. A wide spectrum of tools and techniques can now map connections between neural circuits. Using animal models, scientists have shown how circuits in the brain can be turned on and off. For example, researchers can see correlations between the firing patterns of neurons in a zebrafish’s brain and precise behavioral responses such as seeking and capturing food.

Potential opportunities to influence the brain’s circuitry are starting to emerge. Optogenetics is an experimental technique that involves the delivery of light-sensitive proteins to specific populations of brain cells. Once in place, these light-sensitive proteins can be inhibited or stimulated by exposure to light delivered via fiber optics. Optogenetics has never been used in people, however the success of the approach in animal models demonstrates a proof of principal: A neural network can be precisely targeted.

Thanks in part to the BRAIN Initiative, research on neural circuitry is gaining momentum. The “Brain Research through Advancing Innovative Neurotechnologies” Initiative is accelerating the development and application of new technologies that enable researchers to produce dynamic pictures of the brain that show how individual brain cells and complex neural circuits interact at the speed of thought.

BRAIN is expected to yield tools and technologies that will deepen our understanding of how the nervous system functions in health and disease. These advances are likely to shed light on many neurological diseases, including PD.

"Parkinson's Disease: Challenges, Progress, and Promise", NINDS . September 30, 2015.

NIH Publication No. 15-5595  

Prepared by: Office of Communications and Public Liaison National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda, MD 20892

NINDS health-related material is provided for information purposes only and does not necessarily represent endorsement by or an official position of the National Institute of Neurological Disorders and Stroke or any other Federal agency. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient's medical history.

All NINDS-prepared information is in the public domain and may be freely copied. Credit to the NINDS or the NIH is appreciated.

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Worldwide machine learning contest advances wearable tech for Parkinson's disease

by Tel-Aviv University

Researchers at TAU's Faculty of Medical & Health Sciences invited the international community of machine learning researchers to participate in a contest devised to advance their study and assist neurologists: developing a machine learning model to support a wearable sensor for continuous, automated monitoring and quantification of freezing of gait (FOG) episodes in people with Parkinson's disease. Close to 25,000 solutions were submitted, and the best algorithms were incorporated into the novel technology.

The study was led by Prof. Jeff Hausdorff from the Department of Physical Therapy at the Faculty of Medical & Health Sciences and the Sagol School of Neuroscience at Tel Aviv University, and the Center for the Study of Movement, Cognition and Mobility at the Tel Aviv Medical Center, together with Amit Salomon and Eran Gazit from the Tel Aviv Medical Center. Other investigators included researchers from Belgium, France, and Harvard University.

The paper was published in Nature Communications and featured in the journal's Editors' Highlights.

Prof. Hausdorff, an expert in the fields of gait, aging, and Parkinson's disease, explains, "FOG is a debilitating and so far unexplained phenomenon, affecting 38–65% of Parkinson's sufferers. A FOG episode can last from a few seconds to more than a minute, during which the patient's feet are suddenly 'glued' to the floor, and the person is unable to begin or continue walking.

"FOG can seriously impair the mobility, independence, and quality of life of people with Parkinson's disease, causing great frustration, and frequently leading to falls and injuries."

Amit Salomon adds, "Today the diagnosis and tracking of FOG are usually based on self-report questionnaires and visual observation by clinicians, as well as frame-by-frame analysis of videos of patients in motion.

"This last method, currently the prevailing gold standard, is reliable and accurate, but it has some serious drawbacks: it is time consuming, requires the involvement of at least two experts, and is impracticable for long-term monitoring in the home and daily living environment. Researchers worldwide are trying to use wearable sensors to track and quantify patients' daily functioning. So far, however, successful trials have all relied on a very small number of subjects."

In the current study, the researchers collected data from several existing studies, relating to over 100 patients and about 5,000 FOG episodes. All data were uploaded to the Kaggle platform, a Google company that conducts international machine learning competitions.

Members of the worldwide machine learning community were invited to develop models that would be incorporated into wearable sensors to quantify various FOG parameters (e.g. duration, frequency, and severity of episodes). A total of 1,379 groups from 83 countries rose to the challenge, ultimately submitting a total of 24,862 solutions.

The results of the best models were very close to those obtained through the video analysis method, and significantly better than previous experiments relying on a single wearable sensor . Moreover, the models led to a new discovery: an interesting relationship between FOG frequency and the time of day.

Co-author Eran Gazit notes, "We observed, for the first time, a recurring daily pattern, with peaks of FOG episodes at certain hours of the day, that may be associated with clinical phenomena such as fatigue, or effects of medications. These findings are significant for both clinical treatment and continued research about FOG."

Prof. Hausdorff says, "Wearable sensors supported by machine learning models can continuously monitor and quantify FOG episodes, as well as the patient's general functioning in daily life. This gives the clinician an accurate picture of the patient's condition at all times: has the illness improved or deteriorated? Does it respond to prescribed drugs?

"The informed clinician can respond promptly, while data collected through this technology can support the development of new treatments. In addition, our study demonstrates the power of machine learning contests in advancing medical research .

"The contest we initiated brought together capable, dynamic teams all over the world, who enjoyed a friendly atmosphere of learning and competition for a good cause. Rapid improvement was gained in the effective and precise quantification of FOG data. Moreover, the study laid the foundations for the next stage: long-term 24/7 FOG monitoring in the patient's home and real-world environment."

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Recent Advances in Drug Therapy for Parkinson's Disease

Hidetomo murakami.

1 Department of Neurology, the Jikei University School of Medicine, Japan

Tomotaka Shiraishi

Tadashi umehara, shusaku omoto.

2 Department of Neurology, the Jikei University Katsushika Medical Center, Japan

Yasuyuki Iguchi

Parkinson's disease (PD) is a neurodegenerative disease manifesting with motor and non-motor symptoms. Current treatment mainly relies on medication as a symptomatic therapy modulating neurotransmitters. Dopamine replacement therapy has been established, and levodopa is the gold standard for treatment of PD. However, the emergence of motor complications, such as a wearing-off phenomenon, is a clinical problem. Both primary symptoms and motor complications have been targets for the development of treatments for PD. Recent progression in the management of motor complications is supported by newly developed agents and advances in device and formulation technology to deliver drugs continuously. Elucidation of the pathophysiology of PD and the development of disease-modifying therapy that affects the underlying fundamental pathophysiology of the disease are also progressing. In this review, we introduce current knowledge on developments concerning medications for patients with PD.

Introduction

Parkinson's disease (PD) is a neurodegenerative disease manifesting with motor symptoms of akinesia/bradykinesia, tremor, and muscle rigidity as a triad, together with various non-motor symptoms. The number of patients with PD has increased rapidly with the aging of the population, and this is now referred to as a Parkinson pandemic.

Advances in treatment are anticipated, but current approaches mainly rely on drug therapy as symptomatic therapy modulating neurotransmitters in the brain. Degeneration of nigrostriatal dopaminergic neurons is the most common pathological finding in PD. Therefore, dopamine replacement therapy is the most fundamental treatment for PD patients. However, dopaminergic treatment for several years results in complications, such as the wearing-off phenomenon, which has prompted the development of symptomatic therapies. In the first section of this review, we introduce current drugs used for the symptomatic treatment of PD.

The pathophysiology of PD, such as the cause of neuronal damage, is becoming increasingly clear. Thus, the development of disease-modifying therapy that affects the underlying pathophysiology of the disease is ongoing. In the second section of the review, we introduce candidate disease-modifying drugs currently in phase 2 or more advanced clinical trials.

I. Symptomatic Therapy

Dopamine deficiency in the striatum of PD patients was first reported in the 1960s, and levodopa was developed as a drug that improves both the symptoms and life prognosis of patients ( 1 ). This drug is still the gold standard for treating PD. However, by the mid-1970s, it became apparent that motor complications, such as a wearing-off phenomenon, appear after using levodopa for several years ( 2 ). To date, reduction of these complications has been a focus of drug development for PD. To compensate for the shortcomings of levodopa, drugs with various mechanism of action have been developed. These include dopamine agonists that stimulate neuronal dopamine receptors, monoamine oxidase-B (MAO-B) inhibitors that inhibit metabolism of dopamine in the brain, and catechol-O-methyl transferase (COMT) inhibitors that inhibit degradation of levodopa in the periphery. In this section of this review, we introduce drugs currently being used for symptomatic treatment of PD.

1. Levodopa

1) problems with current levodopa treatment.

Levodopa is the most reliable anti-PD drug for improvement of motor symptoms. However, the half-life of levodopa in blood is short (about 90 minutes), which causes fluctuations in blood levels that result in changes in clinical symptoms in the advanced stage, manifesting as the wearing-off phenomenon. Thus, the development of levodopa therapy with a longer half-life using a different route of administration or formulation is being examined.

Neurotoxicity of levodopa was also suggested in the 1990s, which decreased the use of the drug for some time. However, it is now clear that neurotoxicity does not occur at the dose used in clinical practice, and the use of levodopa has since been reestablished. This return to use of levodopa is also partially due to the influence of advances in device and formulation technology that allow for continuous dopaminergic stimulation (CDS) with levodopa, as shown by the following representative formulations.

2) Levodopa/carbidopa intestinal gel

To overcome the short half-life of levodopa and improve motor symptoms during daytime activity, levodopa/carbidopa intestinal gel (LCIG) was developed. The drug is continuously infused into the upper jejunum through gastrostomy during daytime activities. LCIG was approved in Japan in 2016. In a study in East Asian patients with ≥3 hours off-time per day, use of LCIG shortened the off-time by 4-5 hours and extended the on-time without harmful dyskinesia by 5-6 hours ( 3 ).

3) Sustained release preparation of levodopa

A sustained release capsule preparation (IPX066) packed with levodopa/carbidopa beads with a variety of fast to slow rates of dissolution in the gastrointestinal tract was developed to maintain the blood levodopa level longer than that using immediate release tablets. In a phase III study, the off-time was significantly shortened by IPX066 compared to immediate release tablets ( 4 ). Use of IPX066 has already been approved in western countries, but not in Japan.

4) Levodopa inhalant

A levodopa inhalant (CVT-301) has been approved in the US, but not in Japan, as a rescue medication during off-time. Levodopa is inhaled and rapidly absorbed from the lung. In a phase III study of inhalation of an 84-mg capsule, containing 42 mg of levodopa, motor symptoms during off-time tended to be improved after 10 minutes and were significantly improved after 30 minutes, compared with those before inhalation ( 5 ).

5) Other levodopa formulations under development

Levodopa formulations currently under development include an Accordion Pill Ⓡ capsule utilizing a drug delivery system with a biodegradable polymeric film. The capsule is loaded with a folded multilayer film including levodopa/carbidopa. The ingested capsule dissolves in the stomach, and the folded film opens into a sheet shape and stays in the stomach for a maximum of 12 hours. Gradual release of levodopa/carbidopa from the film maintains a stable blood level, and the film is dissolved in the intestine after completion of drug release ( 6 ). A continuous subcutaneous levodopa injection (ND0612), of which efficacy to reduce fluctuations in plasma concentrations was shown in a phase 2 study ( 7 ), for PD patients with off-time is also under development. Phase 3 studies of both formulations are underway as of July 2021.

2. Monoamine oxidase-B inhibitors

1) novel mao-b inhibitors.

MAO-B inhibitors increase the amount and duration of action of dopamine through inhibition of dopamine metabolism by MAO-B in the brain. In Japan, selegiline was approved in 1998 and has now been used for more than 20 years, while rasagiline was approved in 2018 and safinamide in 2019 as new MAO-B inhibitors. Single-agent administration of rasagiline at a dose of 1 mg/day improves motor symptoms in early-stage PD patients ( 8 ), and addition of 0.5 or 1 mg/day rasagiline significantly shortens the off-time and improves motor symptoms in advanced stage PD patients with motor complications under oral levodopa treatment ( 9 ). Safinamide extends the on-time and decreases the off-time in PD patients with a wearing-off phenomenon not accompanied by problematic dyskinesia and also improves motor symptoms during on-time ( 10 ). Selegiline, rasagiline and safinamide have different characteristics ( Table 1 ), so selecting the most appropriate MAO-B inhibitor is now feasible. For example, safinamide has non-dopaminergic activity, including inhibitory effects on sodium channels and glutamate release, indicating a probable inhibitory effect on dyskinesia ( 11 ). However, the accumulation of further knowledge concerning appropriate use of MAO-B inhibitors is required.

Characteristics of MAO-B inhibitors.

2) Monotherapy with a MAO-B inhibitor for de novo PD

Selegiline was initially developed as an antidepressant in the 1960s. Its utility for motor symptoms of PD was first reported in the mid-1970s, and selegiline has become used mainly as an adjuvant of levodopa ( 12 ). In Japan, selegiline was approved in 1998 for concomitant use with levodopa. Administration of selegiline without levodopa activates the patient's endogenous dopamine, and overseas studies conducted before the approval of selegiline in Japan suggested that improvement of motor symptoms was acquired with monotherapy in patients with early PD ( 13 ). In Japan, administration of selegiline without concomitant levodopa was approved for health insurance coverage in 2011, enabling monotherapy.

MAO-B inhibitors were initially described as an option for first-line treatment in the 2018 edition of the Japanese guidelines for treatment of PD. MAO-B inhibitors have beneficial effects in addition to direct improvement of motor symptoms. Thus, initiation of early treatment with selegiline delays the time at which levodopa becomes necessary, compared with placebo ( 14 ), and concomitant use of selegiline within six months after treatment initiation with levodopa improves long-term motor symptoms and keeps the required dose of levodopa at a low level ( 15 ). Reduced aggravation of activities of daily living (ADL) and gait by using selegiline or rasagiline from the early stage has also been reported ( 16 ). These findings suggest a neuroprotective effect of MAO-B inhibitors, but this has not been shown clinically. In the PD-MED study ( 17 ), the clinical course was investigated based on the drug used for early treatment. Patients treated without levodopa had a lower rate of dyskinesia during a maximum seven-year course than those who received levodopa, and there were also fewer motor complications in non-levodopa cases treated with MAO-B inhibitors compared to dopamine agonists ( 17 ).

MAO-B inhibitor monotherapy is useful, but its effects vary widely among cases. For example, we administered selegiline alone to 28 unmedicated patients with PD and observed a range of improvement in motor symptoms that varied from high to low among cases ( 18 ). Improvement of motor symptoms by MAO-B inhibitor monotherapy as first-line treatment may be poor and lead to the requirement for concomitant levodopa or a dopamine agonist in some cases, but use of a MAO-B inhibitor from the early stage may be significant for the long-term course. A combined formulation of rasagiline and pramipexole, which has an effect complementary to the MAO-B inhibitor, is currently being developed for first-line treatment of PD ( 19 ). Further discussion of the positioning of MAO-B inhibitors as first-line treatment is needed.

3. COMT inhibitors

Entacapone is a COMT inhibitor that promotes levodopa entry into the brain by inhibiting metabolism of levodopa by COMT in the periphery. Entacapone has been used for several years in Japan, and opicapone was approved as a second COMT inhibitor in 2020. In patients with PD with motor complications under treatment with oral levodopa, opicapone significantly shortened the off-time and extended the on-time without accompanying harmful dyskinesia at both doses of 25 and 50 mg/day compared with placebo ( 20 ). The long duration of action of opicapone permits once-a-day administration that supports levodopa activity at all time points. In contrast, entacapone has a relatively short duration of action that requires the drug to be taken simultaneously with levodopa at each time point. Appropriate use based on the status of each patient and characteristics of the drugs is required.

4. Dopamine agonists

Many dopamine agonists came into practical use in the 1980s to 1990s. Since these drugs have longer half-lives than levodopa and a low incidence of motor complications after early treatment, dopamine agonists are recommended to deal with the wearing-off phenomenon in early treatment and the advanced stage. Ergot-derived dopamine agonists were first used, but the main dopamine agonists have changed to non-ergot-derived drugs, as a risk of fibrosis, such as valvular disease of the heart, was pointed out with the earlier drugs. Sustained release preparations of two non-ergot-derived drugs, pramipexole and ropinirole, were produced with the aim of achieving CDS, and a patch capable of maintaining a stable blood level by once-a-day replacement has also been developed. In Japan, a rotigotine patch was approved in 2013 and a ropinirole patch was approved in 2019, increasing the options for dopamine agonists. The affinity for receptor subtypes varies among these agonists, and different clinical effects may be expected. Furthermore, an overnight switch between dopamine agonists is possible, whereas 2-week withdrawal is necessary when switching MAO-B inhibitors. This is useful for selecting the most appropriate drug for each patient, and the safety of switching has also been shown for the recently approved ropinirole patch ( 21 ).

Other advances in dopamine agonists include approval by the Food and Drug Administration (FDA) in 2020 of a sublingual film formulation of apomorphine that can be easily handled. Continuous subcutaneous injection of apomorphine has already been approved in western countries. Whereas, only subcutaneous injection is approved in Japan as a rescue medication during off-time. In addition, most dopamine agonists developed for PD treatment mainly stimulate the dopamine D2 receptor, but an agonist with affinity for the D1/D5 receptor, tavapadon, is now under development ( 22 ), with a phase III study underway as of July 2021.

5. Adenosine A2A receptor inhibitors

Istradefylline received the first approval worldwide in Japan in 2013 as an inhibitor of the adenosine A2A receptor in the indirect pathway in the relatively hyperfunctional state among patients with PD. The indication is for improvement of the wearing-off phenomenon in PD under treatment with a regimen including levodopa, but an off-time shortening effect has also been observed, and this use was approved by the US FDA in 2019.

6. Amantadine sustained release

Amantadine, which was introduced as an agent for type A influenza in the 1970s, inhibits dyskinesia by inhibition of the N-methyl-D-aspartate (NMDA) receptor. This drug was also approved by the FDA in 2017 in a sustained release formulation (amantadine 274 mg capsule), after a demonstration of the efficacy of this formulation in the EASE LID study ( 23 ). Sustained release of amantadine also improves motor symptoms during off-time in patients with PD with motor complications under treatment with levodopa ( 24 ), and this indication was added by the FDA in 2021.

7. Therapeutic drugs for psychosis

PD may be accompanied by hallucinations and delusions, and aggravation of motor symptoms by drugs interfering with the dopaminergic system is a concern. Pimavanserin, an inverse agonist of the 5-HT2A receptor, was approved in the US in 2016 for the treatment of hallucinations and delusions related to neurologic manifestations in patients with PD.

II. Disease-modifying Therapy

PD is a heterogeneous disease for which the pathophysiology is increasingly becoming understood. This includes dysfunction in mitochondria or lysosomes, formation of toxic aggregates of α-synuclein, neuroinflammation, oxidative stress, and other issues. These events are all potential targets of disease-modifying therapy that affects the underlying fundamental pathophysiology of the disease. Numerous studies have attempted to identify medications to inhibit progression of PD, and new compounds are under development. Drugs already used to treat other conditions and related disorders in clinical practice are also being repurposed as agents to treat PD in a process referred to as ‘drug repositioning’. Such repositioning of already approved drugs can save costs and time compared to the development of new drugs. In the second section of the review, we introduce candidate disease-modifying drugs currently in phase 2 or more advanced clinical trials. A summary of these drugs is shown in Table 2 .

Candidate Disease Modifying Therapy for PD Currently in Phase 2 or More Advanced Clinical Trials.

1. α-synuclein targeting therapy

1) immunization for α-synuclein.

α-Synuclein is a 140-amino acid protein that is encoded by the synuclein alpha (SNCA) gene. The physiological role of α-synuclein is unclear, but its aggregation is toxic for neurons ( 25 ). The α-synuclein oligomer causes mitochondrial dysfunction, endoplasmic reticulum stress, proteostasis dysregulation, synaptic impairment, cell apoptosis and neuroinflammation ( 26 ). Cell-to-cell propagation of α-synuclein through prion-like spread is considered to be a pathophysiology of PD, and this propagation may occur during secretion of α-synuclein by exosome exocytosis and endocytosis. According to Braak's theory ( 27 ), the pathology of α-synuclein aggregation is proposed to begin in the medulla and spread gradually to the brain. Therefore, removal of extracellular α-synuclein may prevent progression of the pathology and/or clinical symptoms of PD.

Immunization with anti-α-synuclein oligomer monoclonal antibodies is currently being explored. For passive immunization, BIIB054 (cinpanemab), a monoclonal antibody that binds to the oligomeric and fibrillary forms of α-synuclein, showed good tolerability and safety in a phase 1 trial ( 28 ), but the development of BIIP054 was halted in 2021 because of a lack of efficacy in the primary outcome of improvement of motor symptoms in the phase 2 (SPARK) study. PRX002 (prasinezumab) is also a monoclonal antibody directed against aggregated α-synuclein. The safety and tolerability of PRX002 have been shown in a phase 1 study ( 29 ) and PRX002 is currently in phase 2 trials for PD (PASADENA study and PADOVA study). As an active vaccine for α-synuclein, PD01A, which mimics the C-terminal region of α-synuclein, has shown safety and tolerability in PD patients ( 30 ), and the AFFiRiS Corporation stated in 2020 that a phase 2 trial of PD01A for PD was in preparation.

2) Inhibitor of misfolding of α-synuclein

NPT200-11 inhibits misfolding of α-synuclein and subsequently inhibits its accumulation. NPT200-11 (UCB0599) and related compounds were developed through structure-based drug-discovery that utilized dynamic molecular modeling to identify and target specific regions of the alpha-synuclein protein critical for the formation of misfolded oligomers ( 31 , 32 ). Experiments using transgenic mice overexpressing human wild-type α-synuclein showed that NPT200-11 reduced α-synuclein pathology in the cortex, reduced associated neuroinflammation (astrogliosis), normalized striatal levels of the dopamine transporter (DAT) and improved the motor function ( 32 ). Currently, a phase 2 study of the effects of NPT-200 on the motor and cognitive function and DAT imaging findings in patients with early PD is ongoing.

2. Enhancers of β-glucocerebrosidase

1) β-glucocerebrosidase in pd.

β-glucocerebrosidase (GBA) is a lysosomal enzyme that cleaves glucocerebroside into ceramide and glucose by hydrolysis. Genetic variants of GBA are associated with Gaucher disease and PD. Decreased GBA activity results in the accumulation of glucocerebroside in neurons, which mediates decreased lysosomal activity, formation of toxic α-synuclein oligomers and consequent higher risks of developing PD, more severe disease and faster progression of the disease. Drugs that affect the GBA function are under development.

2) Ambroxol

Ambroxol is an expectorant that has been shown to improve GBA activity in cells carrying GBA mutations and lysosomal activity in cells from patients with GBA mutation-linked PD ( 33 ). In the AiM-PD study, a non-randomized and non-controlled study, treatment with ambroxol improved the motor function of PD patients with and without GBI-1 mutations ( 34 ). A phase 2 study of the effects of ambroxol on the cognitive and motor function and cerebrospinal fluid and magnetic resonance imaging (MRI) findings in PD is currently underway.

PR001A is injected intrathecally as a gene-replacement therapy using adeno-associated virus 9 (AAV9) to deliver a functional copy of the GBA1 gene to the brain ( 35 ). A phase 1-2a open label trial of PR001A for patients with GBA-associated PD is currently being performed.

LTI-291 is an allosteric modulator of GBA that enhances its activity. The results of a phase 1 trial have been published and showed that LTI-291 is well tolerated ( 36 ). According to an announcement on October 1, 2020, on the company's homepage ( https://www.bial.com/com/ , accessed on September 19, 2021), a phase 2 trial should be ready to start in 2021 ( 37 ).

5) Venglustat (GZ/SAR402671)

Venglustat is a glucocerebroside synthase inhibitor designed to reduce production of glucosylceramide. This “substrate reduction therapy” inhibits an upstream enzyme to reduce pathogenic substrate accumulation and is expected to have therapeutic efficacy for PD with GBA mutations. However, a phase 2 trial of the efficacy of venglustat in PD patients with GBA mutations (MOVES-PD study) did not meet the primary or secondary endpoints. Thus, further follow-up was terminated in 2021.

3. Medication with neuroprotective effects

1) glucagon-like peptide 1 receptor agonists.

Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat type II diabetes mellitus. GLP-1 receptor stimulation has also been shown to protect dopaminergic neurons from neurodegeneration in PD model mice ( 38 ). The proposed mechanism involves enhanced mitochondrial biogenesis, suppression of microglial activation and inflammation, enhancement of autophagy and clearance of aggregated proteins ( 39 ). A phase 2 study of exenatide, a GLP-1 receptor agonist, showed efficacy for motor symptoms and a reduced rate of decline in nigrostriatal dopaminergic neurons using DAT imaging ( 40 ). A phase 3 trial to examine the disease-modifying effect of exenatide in PD is ongoing ( 41 ). Phase 2 trials of other GLP-1 receptor agonists, including semaglutide, liraglutide, lixisenatide, LNY01 and a sustained release form of exenatide (PT320), are also ongoing in PD patients.

2) c-Abl inhibitor

The protein Abelson (c-Abl) is a non-receptor tyrosine kinase that is activated by oxidative and cellular stress. c-Abl plays a role in the pathogenesis of PD, including in the aggregation of α-synuclein and formation of Lewy bodies, autophagic impairment, mitochondrial dysfunction, and activation of microglia ( 42 ). Therefore, inhibition of c-Abl may influence the pathogenesis of PD. Some c-Abl inhibitors are already approved for treatment of chronic myelogenous leukemia, and recent studies in PD model mice suggest that c-Abl inhibitors may have neuroprotective effects ( 42 ). Clinical studies have shown that nilotinib increased the cerebrospinal fluid (CSF) level of homovanillic acid, a dopamine metabolite ( 43 , 44 ), reduced that of α-synuclein oligomers ( 43 ), and improved the motor and cognitive function, suggesting a disease-modifying effect ( 45 ). However, another trial of nilotinib showed no improvement in motor symptoms of PD patients ( 46 ). Two other c-Abl inhibitors - K-0706, which is also under the development for chronic myeloid leukemia, and radotinib - are also in phase 2 clinical trials.

3) Ceftriaxone

Ceftriaxone is a widely used antibiotic that has exhibited neuroprotective functions in an animal model of PD with dementia (PDD) ( 47 , 48 ). Based on these findings, a phase II study to investigate the efficacy and safety of ceftriaxone in patients with mild to moderate PDD is ongoing in Taiwan.

4) Sigma-1 receptor agonist

Sigma-1 receptor is a chaperone protein localized in the mitochondria-associated endoplasmic reticulum membrane. Activation of sigma-1 receptor has neuroprotective effects, such as modulation of toxic intracellular cascades involving calcium ions and anti-inflammatory effects as well as the elevation of neurotrophic growth factors ( 49 ). Agonists of sigma-1 receptor induce autophagy and increase proteostasis capacity ( 50 ) and are candidate therapeutic agents for neurodegenerative diseases ( 51 ), especially PDD ( 52 ). A phase 2 study of blarcamesine (ANAVEX 2-73), a sigma-1 receptor agonist, is ongoing in PDD patients.

4. Anti-oxidative stress drugs

1) iron chelators.

In PD patients, iron accumulates in neurons of the substantia nigra ( 53 ), and the accumulated intracellular iron has a neurotoxic effect due to increased reactive oxygen stress ( 54 ). Therefore, iron chelators may be effective for preventing neuronal damage in PD. A phase 2 trial in 22 patients with mild PD showed that deferiprone, an iron chelator, was able to improve motor symptoms and decrease iron concentrations in the dentate and caudate nuclei ( 55 ). In the FAIRPARK trial, patients who started deferiprone immediately showed a significantly better motor performance at 6 or 12 months than those who started 6 months later ( 56 ). A phase 2 study of the efficacy of deferiprone (FAIRPARK-II study) is currently underway in patients with PD.

2) Analogs of coenzyme Q10

Idebenone is an analog of the well-known antioxidant coenzyme Q10 (CoQ10) and has been shown to mitigate motor impairment and to increase the neuron survival in PD model animals ( 57 ). Clinical trials of idebenone for protection against the development of PD in patients with rapid eye movement (REM) sleep behavior disorder (SEASEiPPD study) and therapeutic effects on motor and non-motor symptoms in patients with early PD (ITEP study) are ongoing.

3) Myeloperoxidase inhibitors

Oxidative stress is one of the implicated pathogeneses of PD. Myeloperoxidase (MPO) is a reactive oxygen generating enzyme, and MPO-immunoreactive cells are increased in brain regions affected by neurodegeneration in PD ( 58 ). Oxidative stress is associated with neuroinflammation and neural damage in PD, and inhibition of MPO may reduce oxidative stress, neuroinflammation and neuronal damage in PD patients. A phase 2 study of AZD3241 (verdiperstat), a MPO inhibitor, in PD patients showed a reduction in distribution of activated microglia using 11 C-PBR28 positron emission tomography ( 59 ). Other clinical trials for PD were planned, but whether or not the further development of AZD3241 for PD is underway is unclear.

5. Anti-inflammatory agents and immunosuppressants

1) non-steroidal anti-inflammatory drugs (nsaids) and immunosuppressants.

Dysregulated inflammatory and immune systems, in which activated astrocytes, microglia and peripheral immune cells as well as inflammatory cytokines are present, are also implicated in the etiology of PD ( 60 - 62 ). Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) at baseline has been associated with a reduced risk of PD ( 63 ), and among NSAIDs, ibuprofen has been shown to have a particularly marked effect ( 64 ). A population-based case-control study of United States Medicare beneficiaries showed that the use of immunosuppressants, such as azathioprine, and corticosteroids was also associated with a reduced risk of emergence of PD ( 65 ). Therefore, anti-inflammatory drugs and immunosuppressants may have disease-modifying effects in PD. Among immunosuppressants, azathioprine, which reduces the proliferation of B and T cells via the inhibition of nucleic acid synthesis, is widely used in various immune-related disorders in clinical practice. A phase 2 randomized placebo-controlled, double-blind trial of the effects of azathioprine on progression of motor and non-motor symptoms in early PD patients (AZA-PD study) is in preparation ( 66 ).

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and are commonly used in clinical practice to treat dyslipidemia. These drugs have also been suggested to have anti-oxidative and anti-inflammatory effects ( 67 , 68 ) and to reduce intraneuronal α-synuclein aggregation ( 69 ). A population study showed that the continuation of lipophilic statin therapy was associated with a decreased incidence of PD compared to patients with discontinuation of statins ( 70 ). A recent trial showed that lovastatin treatment in patients with early-stage PD was associated with a trend of reduced exacerbation of motor symptoms ( 71 ). These findings suggest that statins are candidates for neuroprotective treatment for PD. A phase 2 trial examining the effect of simvastatin on PD with a wearing-off phenomenon is currently ongoing ( 72 ), and the effects of lovastatin on motor symptoms in early PD patients are being examined in a phase 2 trial.

6. Recovery of the mitochondrial function

Mitochondrial dysfunction is a pathogenesis of PD and believed to be a promising target for disease-modifying therapy ( 73 ). Mortiboys et al. showed that ursodeoxycholic acid, which has been used for the treatment of liver disease for over 30 years, improved the mitochondrial production of adenosine triphosphate (ATP) in an in vitro study using parkin-mutant fibroblasts and LRRK2 G2049S mutant fibroblasts ( 74 ). Ursodeoxycholic acid has also been shown to rescue the function of mitochondria in LRRS2 G2019S carriers in vivo ( 75 ). Therefore, ursodeoxycholic acid may ameliorate the pathophysiology of PD by improving mitochondrial dysfunction. A phase 2 trial to ascertain the effect of ursodeoxycholic acid on mitochondrial activity, progression of motor symptoms and other effects in patients with PD is ongoing ( 76 ).

In this review, we focused on recent developments of symptomatic and disease-modifying therapy for patients with PD. The search for medications for PD has continued with treatment utilizing already existing drugs, as well as the development of new drugs. Levodopa is still the gold standard for PD, but the high prevalence of motor fluctuation with levodopa is a concern. Treatment options for motor fluctuation as symptomatic therapy are being developing with novel agents and advances in device and formulation technology. Disease-modifying therapy is not yet available in clinical practice, but progress in this area is likely as the pathophysiology of PD is further understood, and this approach may become practical in the near future.

The authors state that they have no Conflict of Interest (COI).

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