2024 Impact Award 

Creating Virtual Brains to Study how Parkinson’s Disease and Depression Interact 

One of the most common non-movement symptoms experienced by people with Parkinson’s disease (PD) is depression. While the mental health impacts of PD-associated depression are debilitating on their own, they have also been associated with increased PD severity. This implies that the neurological changes in the brain that cause depression may also affect the progression of PD. Therefore, better understanding this overlap could improve treatment strategies for people with both.  

Henricus Ruhe, MD, PhD, and recipient of a Parkinson’s Foundation Impact Award, will be using sophisticated brain mapping technology to investigate this subject, seeking new ways to personalize treatments for those with depression and PD.  

For this research, he will collaborate closely with Morten L. Kringelbach, PhD, from Oxford University and Gustavo Deco, PhD, from Pompeu Fabra University in Barcelona, who developed the techniques.  

Dr. Ruhe, from his lab at the Radboud University Medical Center in Nijmegen, Netherlands, a Parkinson’s Foundation Center of Excellence, plans to utilize a new neuroscience research tool called whole-brain computational modeling. The science and math involved with this tool is complex, but put simply, this technique allows researchers to take data from a person’s MRI scans and create a digital model of their brain.  

Within each of these models are nodes, small brain areas whose neurons seem to generally activate together. Based on blood flow measured with MRI-data, the interaction patterns between nodes are mapped and measured to track how signaling information flows through the brain. Additional data, such as physical anatomical distances in the brain, will also be used to bolster the models. 

Using previously collected clinical MRI data from people with PD, some with and some without depression, Dr. Ruhe will be able to generate brain models for his testing. By analyzing and comparing them, he hopes to identify how information flow in the brain is altered by depression in PD contexts.  

In addition, in another cohort of PD-patients without and with depression, where MRI scans taken without (OFF) and with (ON) the use of levodopa medication will provide valuable information about how PD treatment affects depressed and non-depressed brains differently. 

These established brain models can then be used to conduct in silico experiments — meaning that instead of working with cells in petri dishes (in vitro) or with live animals (in vivo), the testing is done with computer simulations.  

In these simulations, Dr. Ruhe will aim to modify specific nodes and see how the rest of the brain reacts and reorganizes in response. These disruptions can be designed to mimic medications, estimating how they would work in the brains of people with and without PD-linked depression.  

Performing these perturbations across the different PD brain models and comparing the outcomes will provide: 

• Major insights into which regions are most critical to brain function in PD and depression. 

• What therapies potentially work best for people with PD and depression, improving the scope and effectiveness of personalized treatments in the future.  

Speaking on the importance of this award for his research goals, Dr. Ruhe said, “I am honored to have received this prestigious award. This will help our team and the Parkinson’s community to develop whole-brain models to better understand and preferably modify non-motor symptoms in PD. This will have substantial impact on selections of treatment of depression in PD patients by identifying susceptible brain regions for different forms of treatment.” 

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

2024 Postdoctoral Fellowship 

Charting Brain Wave Changes to Help Treat Levodopa-induced Movement Symptoms 

The dopamine-replacement medication levodopa is used by a majority of people with Parkinson’s disease (PD) to help treat the hallmark movement disorder symptoms. While this routine treatment often provides quality-of-life improvement, continuous use of levodopa can lead to new movement symptoms called levodopa-induced dyskinesia (LID).  

It is estimated that more than half of people who take levodopa for their PD symptoms develop LID, but the neurological reasons behind this phenomenon are still not well understood. 

Jeroen Habets, MD, PhD, and recipient of a Parkinson’s Foundation Postdoctoral Fellowship, seeks to identify brain wave “biomarkers” of LID, highlighting regions of the brain that go awry during LID and could be targeted by magnetic stimulation therapy to reduce or eliminate LID completely. 

The rhythmic patterns of neuron activation in the brain used to achieve tasks like movement, memory recall and much more can be observed and measured as brain waves. Different frequencies — the speed and intensity of the patterns — of brain waves are associated with different mental states and activities, such as the slow, calm delta waves of deep sleep or rapid, intense gamma waves of alertness and agitation. 

Using a machine called a magneto-encephalograph, Dr. Habets will take study participants with PD and visualize the brain wave activity that occurs during bouts of LID.  

By measuring each participant’s normal brain waves patterns and seeing how and where they change during LID, Dr. Habets hopes to find regions that could be targeted for treatment using non-invasive transcranial magnetic stimulation (TMS), which involves using guided magnetic waves to affect brain wave activity.  

Knowing what regions of the brain and which frequencies of brain waves are involved with LID could lead to personalized TMS treatments that alleviate those debilitating levodopa side effects. 

From the lab of Andrea Kühn, MD, at the Charité University Hospital in Berlin, Germany, Dr. Habets is eager to begin his proposed research with the support of the Parkinson’s Foundation fellowship.  

“This work will lead to a better understanding of how dyskinesia develops, and what happens in the upper layers of the brain when people suffer from involuntary dyskinetic movements,” said Dr. Habets. “Besides extending our fundamental knowledge, these findings will help to develop brain stimulation strategies to treat dyskinesia. Potentially, this work will extend our future therapeutic possibilities to help people with Parkinson's disease that suffer from dyskinesia.” 

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

2024 Impact Award 

Searching for Gut Bacteria That May Lead to Parkinson’s Disease 

Research has shown that the trillions of bacteria that live in our gut have incredible influence over our health — offering protection from many illnesses and diseases. Recent studies suggest that alterations in gut bacteria may drive the development or progression of  Parkinson’s disease (PD).  

Gut bacteria have been linked to PD development in different ways, like driving the accumulation of misfolded proteins or even inhibiting the effectiveness of PD medication. However, identifying the specific types, or strains, of bacteria most linked to PD and understanding what attributes they possess to propel the disease has been a daunting challenge for scientists.  

Chris Smillie, PhD, the recipient of a Parkinson’s Foundation Impact Award, is using cutting-edge genetic tools and techniques to comb through trillions of bacterial cells to find the ones most associated with PD. Through his research, he aims to identify how their activity and function may contribute to the disease, and how we might be able to target gut bacteria to slow, stop or prevent PD progression. 

Gut bacteria are highly adaptable microbes, capable of rapid evolution in response to changes in their environment. “Health-adapted” bacteria strains, which thrive in a healthy gut, might offer a protective benefit for the person they live in by fighting off viruses or other invaders. Conversely, “illness-adapted” strains may thrive in environments of gastrointestinal distress, potentially evolving to cause and maintain such distress.  

Following the growing evidence pointing toward gut bacteria affecting PD, Dr. Smillie believes that there are “PD-adapted” bacteria strains that adapt to and consequently cause conditions that progress PD. 

To figure out which bacteria might be PD-adapted, Dr. Smillie and his research team at the Massachusetts General Hospital in Boston, MA, a Parkinson’s Foundation Center of Excellence, will utilize stool samples from nearly 3,000 study participants: some with PD, some without PD as controls, and others with inflammatory bowel diseases (to isolate PD-adaptation from other gut-distressing adaptations).  

After analyzing all the bacterial DNA from these samples, he will use computational tools to find the different strains present as well as map which unique strains are most associated with PD.  

Going further, Dr. Smillie plans to untangle the PD-adapted strains’ evolutionary paths, discovering which genetic changes they underwent over time to become associated with PD. Identifying these changes will also help him understand the functional connections between the strains and PD, uncovering mutations in bacterial proteins that may contribute to disease progression. 

After amassing this staggering amount of genetic data about PD-adapted bacteria, Dr. Smillie hopes his research will provide scientists and doctors with new ways to diagnose and treat PD earlier, by looking at the gut instead of the brain.  

On receiving this award and the impact of his proposed research, Dr. Smillie said “The Parkinson's Foundation Impact Award is an immense honor. With this award my lab will apply powerful computational tools to identify the bacteria that are associated with Parkinson's, which will yield new insights into disease mechanisms, and may guide the development of microbiome-based therapeutics to treat the disease or its gut symptoms.” 

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

2021 Postdoctoral Fellowship
2024 Launch Award

Illuminating the Neurobiology Behind Impulsivity Associated with Parkinson’s Medication  

Studies estimate that at up to 40% of people taking dopamine-related drugs to treat Parkinson’s disease (PD) symptoms develop an impulse control disorder (ICD) as a side effect of the medication. While this phenomenon is likely related to dopamine’s role in reward-seeking decision-making in the brain, the specific biological patterns involved are still not fully understood.  

Xiaowen Zhuang, PhD, recipient of a Parkinson’s Foundation Launch Award and previous Postdoctoral Fellow, will be utilizing her new mouse model of ICD, along with complex brain analysis and manipulation technology, to shed light on the neurobiology of the condition. She hopes this research can inspire future PD treatments that avoid the side effect altogether. 

In humans, ICD can present in many ways such as binge eating, impulse shopping or excessive gambling. To study impulsivity in lab animals, researchers often measure what is known as delay discounting behavior, reflecting the subject’s ability to weigh reward value against the time required to receive it. High impulsivity results in high delay discounting, favoring a smaller immediate reward to a larger delayed reward.  

Under the mentorship of Dr. Alexandra Nelson at the University of California, San Francisco, CA, a Parkinson’s Foundation Center of Excellence, Dr. Zhuang will use a delay discounting experiment for mice which measures how long they are willing to wait for a larger reward of food, or conversely how impulsive they act in taking a smaller reward right away.  

Previously, she used this test on healthy mice and mice with PD-like neurodegeneration taking dopamine medication. The major finding was that the latter group showed increased impulsive behavior, taking the smaller immediate rewards significantly more often than the healthy mice. 

Building upon these preliminary experiments, Dr. Zhuang will next utilize optogenetics (a biological technique that uses light to turn specific neurons on and off on demand) to test if specific neurons in the striatum region of the brain are responsible for ICD behavior.  

She expects that activating certain neurons and inhibiting others during the tasks will make the mice more impulsive, confirming the neurons’ relevance to the condition.  Dr. Zhuang will also use her optogenetic tools to determine if altering the neurons’ synaptic plasticity — their adaptive increase or decrease in ability to receive signals — can contribute to impulsive behavior as well. 

These in-depth experiments will greatly add to our understanding of how brain changes during PD treatment may cause ICD, providing valuable insight into how future medicines might prevent or remedy such side effects.  

Discussing what this support means to her research and professional development, Dr. Zhuang said, “This award will lead me to be able to ask questions in the field of cognitive deficits of PD with a focus on impulsivity using a multi-disciplinary approach. The findings gained from this research will not only provide greater insight into the synaptic mechanisms of ICD, but also inform the use of dopamine replacement therapy with a goal of preventing or ameliorating impulse control disorders.” 

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

2024 Postdoctoral Fellowship 

Uncovering a Missing Link Between Genetic Mutation and Protein Clumping in PD 

Several genetic mutations linked to the development of Parkinson’s disease (PD) have been discovered over decades of research. However, fully understanding how those mutations can cause PD is an ongoing scientific challenge.  

Learn more about PD GENEration: Mapping the Future of Parkinson's Disease, which offers genetic testing and counseling at no cost for people with PD.

One such PD-associated mutation leads to the production of a malfunctioning version of the protein LRRK2. Faulty LRRK2 is believed to disrupt several important processes within neurons and consequently contribute to PD progression, but how exactly these disruptions lead to the disease is still being studied.  

Silas Buck, PhD, recipient of a Parkinson’s Foundation Postdoctoral Fellowship, believes a relatively understudied protein may be affected by mutant LRRK2 and drive PD-related cellular breakdown. Through his experiments, he will seek to understand how this protein (called HDAC6) is corrupted in LRRK2-associated PD and how we might use this knowledge to create new treatments that prevent disruption to slow the disease. 

When looking at the posthumous brain tissue of people who had LRRK2-mutant PD, scientists have routinely seen unhealthy aggregates or clumps of a protein called tau. Similar to alpha-synuclein clumping, tau clumping is believed to contribute to the disease-related breakdown of dopamine neurons and is associated with PD dementia. HDAC6 is a protein with many responsibilities, one of which is to regulate tau and keep it from clumping. However, Dr. Buck hypothesizes HDAC6 may be a missing link connecting LRRK2 to tau clumping in PD. 

“Determining the potential positive effect of HDAC6 inhibition in Parkinson’s disease could have an immediate impact on people with Parkinson’s disease,” said Dr. Buck. 

Dr. Buck, working in the lab of Dr. Laurie Sanders at the Duke University School of Medicine in Durham, NC, a Parkinson’s Foundation Center of Excellence, will be conducting research to see if and how mutant LRRK2 causes disruptions in HDAC6 that lead to PD-associated tau clumping. Using neurons grown in petri dishes, Dr. Buck will first measure how much LRRK2 and HDAC6 interact in healthy brain cells.  

Then, he will introduce mutant LRRK2 into those cells and analyze how that affects the LRRK2-HDAC6 interactions and if such changes result in tau clumping. Finally, Dr. Buck will investigate if mutant LRRK2’s impact on HDAC6 also contributes to disrupted mitochondria repair and cleanup, another cellular stressor commonly seen in PD brain tissue.  

Uncovering more biochemical links in the chain between gene mutation and PD means more opportunities to intervene in the disease’s progression. Through Dr. Buck’s experiments, we will understand more about HDAC6’s role in PD development and how it could be the target of new future therapies, expanding the effective medication options and improving doctors’ ability to provide genetically personalized treatment plans for people with Parkinson’s. 

When asked about the personal and scientific impact of this Parkinson’s Foundation support, Dr. Buck said “Receiving this postdoctoral fellowship allows me to pursue my passion of performing exciting and important research that could one day help substantially improve the lives of people with Parkinson’s disease. It has always been my dream to make a difference in the health of others through research, and I hope to achieve that through this project.” 

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

2024 Postdoctoral Fellowship 

Investigating How Parkinson’s Derails Crucial Transport Routes Within Neurons 

Neurons, the cell type that transmits information in our brain and nervous system, are complex in ways that have puzzled researchers for decades. Depending on their location and role in the body, neurons can vary wildly in shape and activity, with some stretching up to a meter in length to perform their signaling duties. Their unique form and function also create challenges for neurons, having to manage cellular upkeep across long distances to stay fit and functional.  

The dopamine-producing neurons in the brain progressively lost in Parkinson’s disease (PD) are no exception. How the disease may impact the cells’ critical maintenance is still not well understood. Inés Patop, PhD, recipient of a Parkinson’s Foundation Postdoctoral Fellowship, will be utilizing new and sophisticated biological tools to improve our understanding of not just how PD may affect neuronal upkeep, but specifically where it is most damaging within the cell and how we can use that knowledge to design more efficient therapies. 

While their shape and size vary across the body, all neurons are composed of two distinct parts:  

1. The soma: the larger main area of the cell that contains the DNA-storing nucleus 

2. The neurites: the tendril-like extensions that reach out to other cells to either receive signals (as dendrites) or convey signals (as axons).  

In each of these parts are mitochondria, miniature cell powerplants that require routine maintenance to keep the cell working properly. Parkinson’s disease has been associated with mitochondria misfunction for more than 30 years, being most of the PD-associated mutations involved in the process of clearing defective mitochondria.  

The trick is that the blueprints needed for proper mitochondrial function and to repair and clear defective mitochondria come from the nucleus in the soma, so to maintain or clear the far-away mitochondria in the neurites, the neuron needs to print and transport those blueprints (called RNA) across the cell. That process requires significant coordination to execute properly, coordination that is likely disrupted in neurons affected by PD-associated mutations.  

From the lab of Dr. Stirling Churchman at Harvard University in Boston, MA, Dr. Patop will utilize special growing chambers that will allow them to isolate and study the soma and neurites of neurons individually. They will then run complex biochemical analyses to see how RNA printing and transport, mitochondria repair and more differ between the distinct cell regions, and how each is affected by PD mutations. From this data, Dr. Patop hopes to better understand how PD may affect neurons differently from soma to dendrites, potentially leading to new future treatments that target the most impacted regions of the cells. 

When asked what the Parkinson’s Foundation research funding means to them, they said, “I am confident this opportunity will lay a strong foundation for my future career, empowering me to make meaningful contributions to the scientific community and, ultimately, improve the lives of those affected by Parkinson's disease. Through this research, we expect to identify new regulatory mechanisms implicated in PD, potentially identifying novel drug targets for treatment. The impact of this research could significantly advance our understanding of PD and pave the way for innovative therapeutic strategies.” 

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