Unity Walk > Parkinson's Foundation Research Grants 2019

 

Parkinson's Foundation is using its 2019 distribution to fund:

Modulation of the inflammatory response in Parkinson’s disease

Network-based imaging biomarkers in Parkinson’s disease with genetic risk factors

 

PROJECT TITLE:  Modulation of the inflammatory response in Parkinson’s disease

Investigators/Authors: Giulietta Riboldi, MD, NYU School of Medicine

Objective: We propose to assess DNA methylation profiles in whole blood (WB) and isolated monocytes from PD patients and controls in order to study the role of the immune system in Parkinson’s disease.

Background:PD is the second most common degenerative disorder worldwide. Despite the identification of many different pathways that may play a central role in this disease, its pathogenic mechanisms are not yet clear. Because of this lack of knowledge, available treatments are mainly symptomatic. Cell-autonomous mechanisms seem to play an important role in the degeneration of the dopaminergic cells, which is the hallmark of the disease. However, microglia activation and its scavenger role in the elimination of alpha-synuclein, the interaction between the T-cell compartment and the role of dopaminergic neurons as antigen presenting cells (APC), all suggest an important role of inflammation in PD.

Methods/Design: Our goal is to profile epigenomic modifications such as DNA methylation in peripheral monocytes. Our rationale is that environmental exposures (smoking, caffeine, alcohol, organophosphate) and biophysical features (such as urate and flavonoids levels, hormonal therapy, physical activities) affect the incidence of PD. Environmental exposure may affect the epigenetic profiles of target tissues and modulate the inflammatory response through their effect on specific cell types.

We will recruit a population of 50 well characterized PD patients and 50 controls (defined as age- matched subjects that do not carry a diagnosis of neurodegenerative disease or chronic autoimmune disorder) and assess their exposure to risk factors previously associated with PD. Collected data will be used to define PD phenotypes and will be correlated with genome wide DNA methylation from isolated CD14+ monocytes. In addition, we aim to perform an integrated genomic analysis to correlate methylation profiles, expression profiles and genotype in whole blood from a large cohort (PPMI study) of PD patients and controls. These analyses will identify impaired pathways and signatures of the disease. Additionally, deconvolution analysis of our data will be performed to detect the contribution of different subpopulations of cells of the immune system to be then confirmed in isolated CD14+ monocytes. Lastly, we will generate genome-wide DNA methylation profiles from CD14+ monocytes in a pilot cohort of PD and control subjects.

Relevance to Diagnosis/Treatment of Parkinson’s disease: The project will help elucidate the role of the immune system in PD. DNA methylation signatures in blood cells could represent an easily accessible biomarker for the diagnosis, phenotypical stratification, and assessment of novel therapies for PD.

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PROJECT TITLE:  Network-based imaging biomarkers in Parkinson’s disease with genetic risk factors

Investigators/Authors:  Katharina Schindelbeck, MD, Feinstein Institute for Medical Research

Objective: We have previously identified and validated imaging network biomarkers to assess the progression of motor and cognitive dysfunction in PD patients using metabolic PET-based as well as functional MRI (fMRI)-based methods. We propose to compare these PET-based and fMRI-based biomarkers in PD patients with and without GBA variants to determine if there are specific network changes associated with GBA mutations that could be used as a biomarker.

Background: Although PD is usually idiopathic, there are individuals with genetic risk factors. Of these, mutations in the GBA gene encoding the enzyme glucocerebrosidase are among the most common. Indeed, individuals carrying GBA mutations as well as the E326K polymorphism can develop PD that is pathologically and clinically indistinguishable from the sporadic disease. These patients, however, tend to experience earlier symptom onset and more rapid disease progression than PD patients without GBA mutations. The relationship between reduced GBA activity and faster disease progression in these patients suggests a potential role for this pathway as a target of disease-modifying therapy.

Methods/Design: We will use PET imaging and resting state fMRI to assess the expression of PD-related motor and cognitive disease network patterns in matched groups of PD patients with and without GBA variants. We will: a) Correlate expression values for these networks with motor and neuropsychological ratings obtained for individual subjects; b) Compare and optimize PD network biomarkers derived using PET and fMRI; and c) Determine whether GBA(+) PD subjects express additional networks independent of the PD motor and cognitive patterns that shed light on their more severe clinical features. We will also assess longitudinal changes in the expression of PD-related motor and cognitive disease network patterns in the GBA(+) and GBA(-) PD patients by scanning them at baseline and 18 months later. We will: a) Compare network progression rates for the two groups; b) Correlate network progression in each group with concurrent changes in clinical ratings measured in the same subjects; and c) Validate the PD-related networks as progression biomarkers.

Relevance to Diagnosis/Treatment of Parkinson’s disease: This study will identify the network biomarker that is most sensitive to disease progression in GBA mutation-positive Parkinson’s disease patients. These determinations will be critical for the design of clinical trials of new disease-modifying drugs.

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