Pants Sign as a Predictive Marker for Postural Inability and Falling in Parkinson's Disease

Changes in Action Tremor in Parkinson's Disease over Time Clinical and Neuroimaging Correlates

Main applicant: Kevin van Den Berg

Affiliation(s): Radboudumc (NL)

Abstract: The various symptoms of Parkinson's disease (PD) may change differently over time as the disease progresses. Tremor usually manifests early in the disease, but unlike other motor symptoms, its severity may diminish over time. The cerebral mechanisms underlying these symptom-specific longitudinal trajectories are unclear. Previous magnetic resonance imaging (MRI) studies have shown structural changes in brain regions associated with PD tremor, suggesting that structural changes over time may define clinical trajectories.

Vitamin B6, B9, and B12 Intake in Relation to Parkinson's Disease Progression in Patients on Levodopa Medication A Data-Driven Identification Approach via Copula Graphical Modelling

Main applicant: Dr. Pol Grootswagers

Affiliation(s): Wageningen University (NL)

Abstract: Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease, which has severe consequences, as it is chronic and incurable. Previous research shows that some B-vitamins are associated with decreased risk of PD. However, the role of B-vitamin intake on the progression of PD, such as cognitive- and motor functioning, remains unclear. Vitamin B6, B9, and B12 are involved in the homocysteine (Hcy) metabolism, and sufficient intake relates to lower Hcy levels. Hcy levels are increased in PD patients and have been linked to cardio- and cerebrovascular events and reduced cognitive function. Lower Hcy levels and higher vitamin B6, B9, and B12 intake could therefore slow the progression of PD.

Research question: This thesis investigates the individual associations between vitamin B6, B9, and B12 intake via food and the progression of PD in patients on Levodopa medication.

Methods: Data from the Personalized Parkinson Project (PPP) will be used, in which 517 patients ≥ 18 years with PD were included with a PD duration ≤5 years. Of these patients, FFQ data of 253 patients were available for vitamin B intake. Progression is defined as the decline of motor- and cognitive functioning. Motor functioning was measured with the Movement Disorders Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale from the motor section (part III) in the OFF and ON state. Cognitive functioning was measured with the Montreal Cognitive Assessment scale (MoCA). Linear (mixed) models will be used to answer the research questions. Potential confounders that will be adjusted for are age, Levodopa Dose Equivalency, physical activity, sex, smoking, disease duration, energy intake, protein intake, fiber intake, Body Mass Index, and the other B-vitamins.

Related publications: ‘Role of Diet and Nutritional Supplements in Parkinson’s Disease Progression’ Role of Diet and Nutritional Supplements in Parkinson's Disease Progression - PMC

AADC Enzyme Activity in De Novo Parkinson's Disease

Main applicant: Prof. dr. Marcel Verbeek

Affiliation(s): Radboudumc (NL).

Abstract: Biomarkers for early identification of PD are scarce. Previous studies have shown that persons with PD, between 2 and 12 years of disease duration, have increased blood AADC enzyme activity levels. We aim to study if blood levels of the AADC enzyme activity are also increased in PD patients at early stage of the disease, and may therefore serve as an early biomarker of PD.

Investigating the fPDRP and fPDCP Brain Patterns in Parkinson's Disease

Main applicant: Dr. Rick Helmich, Dr. Amgad Droby and Dr. An Vo

Affiliation(s): Radboud University Medical Center, Nijmegen (NL), Tell Aviv Sourasky Medical Center (IL), Feinstein Institute for Medical Research, Manhasset (US)

Abstract: Currently, the main way to confirm Parkinson's disease (PD) through imaging is by using a special type of scan called dopamine-transporter SPECT (DaT-SPECT). However, DaT-SPECT has some drawbacks, such as being expensive, using radioactive materials, and not being widely available. These limitations make it less effective for monitoring early stages of the disease, which can start up to 20 years before symptoms appear. MRI (Magnetic Resonance Imaging) is a non-invasive alternative that can help study the disease throughout its course. One type of MRI, called resting-state functional MRI (rs-fMRI), measures brain activity by tracking blood oxygen levels. This method can show changes in brain networks due to ongoing disease processes, even before symptoms start. We identified previously specific brain activity patterns related to PD using another imaging technique called FDG-PET. These patterns, known as PD-related patterns (PDRP) and PD cognition-related patterns (PDCP), have been linked to PD symptoms like movement issues and cognitive decline. PDRP shows increased brain activity in certain regions and decreased activity in others, while PDCP is associated with changes in brain areas linked to cognitive functions. Similar brain patterns were identified using rs-fMRI as well, which confirms the brain activity changes seen in FDG-PET scans. In a recent study, we used advanced methods to analyze brain scans from 60 newly diagnosed PD patients and 58 healthy people of the same age and sex. We identified brain patterns that help differentiate between PD patients and healthy individuals with an accuracy of up to 83%. These patterns are linked to both movement and cognitive changes in PD. This project aims to test the AI model on a new group of drug-naive PD patients (De Novo) and healthy controls to see how well it works. Additionally, we seek to validate the identified brain patterns and explore their relationship with clinical performance scores.

Mapping Microstructural Gradients of the Human Striatum in Parkinson's Disease

Main applicant: Dr. Aviv Mezer

Affiliation(s): Hebrew University of Jerusalem (IL)

Abstract: The human striatum undergoes significant alterations in Parkinson's Disease (PD). Although MRI is the predominant method for in vivo imaging of the human brain, identifying PD-related changes through MRI remains challenging. We have developed a tool designed to characterize spatial structural changes in the human striatum in vivo. Utilizing an open-source dataset (PPMI), our analysis has successfully characterized PD. In this proposal, our primary objectives are:

To validate these findings by replicating the results using the PPP dataset.
To investigate whether our analysis can further delineate sub-groups within the PD patient population (based on Johansson et al., NPJ PD 2023, Brain 2024).

Neural Markers of Freezing of Gait in Parkinson's Disease

Main applicant: Asst. Prof. Moran Gilat

Affiliation(s): KU Leuven (BE)

Abstract: This study aims to uncover neural markers of Freezing of Gait (FOG) in Parkinson’s disease (PD). FOG is notoriously difficult to treat once it develops and therefore early risk detection and intervention may be a more effective strategy. So far, research on the neural changes preceding the onset of FOG are limited, due to small datasets with poor FOG characterization. Using clinical and MRI data from the PPP, we will objectively characterize FOG and investigate the structural and functional connectivity changes predictive of future FOG development. We anticipate that this work will uncover novel and generalizable neural markers of FOG risk in PD.

Protein Structural Biomarkers to Predict Motor Progression in Parkinson's Disease

Main applicant: Prof. Dr. Paola Picotti

Affiliation(s): ETH Zurich (CH)

Abstract: Parkinson’s disease (PD) is the second most prevalent neurodegenerative brain disease, becoming more common with the aging of our society. People affected by PD vary widely in prognosis, rate of progression and response to treatment. The ability to predict these differences at the time of diagnosis would significantly improve our ability to give the best care to patients. To date, there are no reliable ways to predict how a person diagnosed with PD will progress. In recent work, we have used our cutting-edge technology to compare the structures (i.e., shapes) of thousands of proteins between the cerebrospinal fluid (CSF) of Parkinson’s patients and healthy individuals. We found that about 100 proteins had different structures in Parkinson’s and healthy CSF. This was a major discovery since nobody had made such a comparison or found such structural changes before. It showed that looking at protein structures can be a powerful way to diagnose Parkinsons’ disease. Now, in this new project, we will apply the same approach to try to discover biomarkers predicting the rate of motor or cognitive decline during disease progression in PD. Such biomarkers would guide physicians in the selection of the best personalized treatment or disease management, help decide which patients to include in clinical studies for testing new treatments, and possibly help us understand the underlying reasons for faster or slower progression.

Related publications: Biomarkers in Parkinson’s disease: Advances and strategies

Changing Rhythms in Parkinson's Disease Development of Motor and Non-Motor Digital Progression Biomarkers Based on Continuous, Real-Life Monitoring

Main applicant: Luc Evers

Affiliation(s): Radboud university medical center, Nijmegen (NL)

Abstract: Although new treatments are being developed to slow the progression of Parkinson’s disease, assessing their effectiveness remains a challenge. Evaluations conducted in the clinic can only provide a periodic “snapshot” of an individual’s condition. Unobtrusive wearable sensors – such as the Study Watch used in the Personalized Parkinson Project – now allow us to capture objectively and continuously how patients function at home, as they go about their daily routines. The goal of this project is to develop the algorithms needed to extract reliable insights from the raw sensor data from the Study Watch. By combining the unique longitudinal data from the Personalized Parkinson Project with data from smaller reference datasets, we are developing AI models to study tremor, gait and heart-rate variability in daily life, and assess their long-term progression. The resulting “digital biomarkers” could pave the way for more efficient clinical trials and more personalized treatment for people with Parkinson disease.

Hidden Sorrows of COVID-19 Impact of Stress on Parkinson's Disease Progression

Parkinson’s disease (PD) is caused by progressive loss of nigro-striatal dopamine cells. Converging clinical evidence indicates that PD patients are very sensitive to the effects of psychological stress.

Main applicant: Dr. Rick Helmich

Affiliation(s): Radboud university medical centre, Nijmegen (NL); Donders Center of Medical Neurosciences, Nijmegen (NL)

Abstract: Parkinson’s disease (PD) is caused by progressive loss of nigro-striatal dopamine cells. Converging clinical evidence indicates that PD patients are very sensitive to the effects of psychological stress. There is a high prevalence of stress-related neuropsychiatric symptoms in PD, and stress worsens many motor symptoms. Moreover, chronic stress may also have detrimental long-term consequences, specifically by accelerating disease progression, as suggested by animal models. In this study, we aim to test the hypothesis that psychological distress accelerates nigro-striatal cell loss in PD, and that this effect is mediated by increased inflammatory tone. In humans, the relationship between chronic stress and rate of PD progression is still unknown: it is unethical to deliberately expose individuals to potentially harmful effects of chronic stress. This knowledge would have major treatment consequences: novel stress-reducing interventions may have symptomatic effects, and perhaps also disease-modifying effects. We and others have previously shown that social isolation measures during the covid-19 pandemic have caused considerable psychological distress in PD patients. Here, we will investigate if and how a real-life stressor (covid-19 pandemic) influences PD progression. Stress hormones (e.g. cortisol) affect major immune functions by increasing microglia activation, which is also present in PD. Neuroinflammation precedes neurodegeneration in the substantia nigra, suggesting a causal relationship. Indeed, previous research has shown that several inflammatory cytokines are increased in the serum of PD patients. Thus, we expect that the detrimental effects of stress on neurodegeneration may be mediated by increased systemic inflammation.

Pants Sign as a Predictive Marker for Postural Inability and Falling in Parkinson's Disease

ABCD-Parkinson Developing a Bisulfite-Sequencing Assay

To estimate the concentration of cell-free DNA (cfDNA) in peripheral blood as a surrogate marker of brain cell degeneration.

Main applicant: Dr. Hieab Adams

Affiliation(s): Erasmus MC, Rotterdam

Abstract: There is a need for accurate disease-progression biomarkers for Parkinson’s disease (PD). Degeneration of the substantia nigra pars compacta (SNc) is a key mechanism underlying progression of PD, but is hard to measure reliably. In this project, we will employ a novel approach to measure SNc degeneration, by focusing on small cell-free DNA fragments (cfDNA) that are released by degenerated cells in the bloodstream. These fragments contain cell-type specific methylation patterns, which make the fragments traceable to their cell-of-origin. cfDNA based methylation assays are novel to the field of PD, but have already been applied successfully in other neurological disorders. We will (a) develop a whole-genome methylation assay to quantify the concentration of SNc-derived cfDNA in peripheral blood as a surrogate marker of SNc degeneration; (b) determine SNc cfDNA concentrations in repeated plasma samples of 130 deeply phenotyped people with PD; and (c) determine whether SNc cfDNA concentrations reflect clinical PD disease duration, as a measure of disease-progression.

Personalized Treatment of Gut Health to Combat Levodopa-Resistance in Persons with Parkinson's Disease

Main applicant: Prof. Marcel Verbeek

Affiliation(s): Radboud university medical center, Nijmegen (NL)

Abstract: Many persons with PD develop small intestinal bacterial overgrowth (SIBO), which negatively affects their quality of life by causing abdominal pains, constipation, bloating, nausea, diarrhea and excessive flatulation. Recent work indicates that SIBO can cause additional problems for persons with PD. Specifically, SIBO is likely associated with overgrowth of specific bacterial subcultures, which produce an excessive amount of the enzyme tyrosine decarboxylase (TDC) in the gut. This TDC enzyme breaks down levodopa (the most important symptomatic drug to treat PD) before it can enter the brain, thus providing a peripheral obstacle that can explain why a significant proportion of patients respond much less favorably to levodopa than others, and why some patients even appear to become resistant to levodopa. This causes tremendous problems in daily clinical practice, because treatment failure of levodopa typically blocks any further attempts to try alternative treatments, thus causing considerable yet avoidable disability. In this project, we aim to: (1) examine whether quantifying levels of the TDC enzyme in the gut may serve as an objective biomarker that would objectively indicate the presence of such a peripheral blockade to levodopa; and (2) evaluate whether two innovative treatment strategies can help to alleviate this ‘peripheral levodopa resistance’. Specifically, our first approach is to seek proof-of-concept evidence that treatment with the antibiotic rifaximin can restore microbiome health and – by reducing gut TDC levels – restore the responsiveness to levodopa. We also expect vancomycin treatment to alleviate the debilitating complaints associated with SIBO. Our second and completely complimentary approach is to leave the gut itself untouched, but instead we aim to bypass the gut blockade by administering the potent dopamine receptor agonist apomorphine via a subcutaneous delivery. We expect that patients who have become partially or completely resistant to oral levodopa due to high TDC activity in the gut will show a gratifying response to apomorphine treatment. If proven to be correct, this could lead to timely instalment of dopamine agonist treatment in daily practice, including subcutaneous apomorphine, but also using less invasive approaches such as subcutaneous patch treatments. Our study will provide critical new insights into the role of peripheral levodopa resistance. Our findings can potentially have important clinical implications, since adequate tackling of this phenomenon using either vancomycin, a subcutaneous dopamine agonist or a combination thereof, could avoid the typically prolonged and time-consuming process of gradual further dose increases in levodopa (which is now common in daily practice). Timely instalment of these new treatment strategies could provide significant benefits to many patients with PD worldwide.

Microbiome-Mitochondrial Interactions Impact Neuronal Circuits and Gut-Brain Connections in Parkinson's Disease (MIGUT)

Drug treatment with levodopa is the mainstay of treatment, but offers only partial symptomatic relief.

Main applicant: Prof. Marcel Verbeek

Affiliation(s): Radboud university medical center, Nijmegen (NL)

Abstract: Parkinson’s disease (PD) is the fastest growing neurological disease worldwide. Drug treatment with levodopa is the mainstay of treatment, but offers only partial symptomatic relief. Moreover, disease progression cannot be stopped. Development of novel therapies aimed at slowing disease progression is hampered by the lack of detailed knowledge of the underlying disease mechanisms. Importantly, multiple mechanisms likely contribute to causing PD, but we do not know how these different mechanisms interact within an individual patient. In this study, a new, comprehensive approach to tackle the complexity of PD, by studying multiple disease mechanisms simultaneously, as well as their interaction, is offered. Using PPP samples, we aim to determine the composition of bacteria in the gut, the presence of signals of metabolism in blood of PD patients, and the function of the energy-generating machinery of our body: the mitochondria. With these analyses, we will obtain detailed information about the disease mechanisms underlying PD, and how these mechanisms interact within an individual patient. We expect that this study can offer a basis for new personalized treatments for PD patients.

Genetic analyses for MIGUT and JPND projects

Development of novel therapies aimed at slowing disease progression is hampered by the lack of detailed knowledge of the underlying disease mechanisms.

Main applicants: Prof. Marcel Verbeek and Dr. Rick Helmich

Affiliation(s): Radboud university medical center, Nijmegen (NL); Donders Center of Medical Neurosciences, Nijmegen (NL)

In the MIGUT project, a new approach to tackle the complexity of PD is offered, by studying multiple disease mechanisms simultaneously, as well as their interaction. We aim to determine the function of the energy-generating machinery of our body: the mitochondria. We will also study the composition of bacteria in the gut, and the presence of signals of metabolism in blood of PD patients. With these analyses, we will obtain detailed information about the disease mechanisms underlying PD, and how these mechanisms interact within an individual patient.

In the JPND consortium, we are interested in understanding why some patients have very widespread dysfunction of the brain, while in others the abnormalities are restricted to a few brain regions. Patients are asked to perform different cognitive tasks; the responses of the patients inform us about which brain areas are affected. This information will be integrated with clinical, genetic, and brain imaging information to determine how these various factors play a role in the degree of brain dysfunction that is observed in individual PD patients.

We expect that these studies can offer a basis for new and timely personalized treatments for PD patients.

Related publications: