Study Rationale:
Parkinson’s disease patients with mutations in the glucocerebrosidase (GBA) gene tend to have a more aggressive disease course. GBA pathways may therefore constitute a discrete target for disease-modifying therapies in mutation carriers. Using imaging to quantify network progression rates in mutation carriers will allow for objective assessment of the potential disease-modifying effects of new anti-GBA therapies.
Hypothesis:
In this longitudinal study, we will follow Parkinson’s disease patients with and without GBA mutations. We hypothesize that the rate of increase in network activity over time (“network progression rate”) is faster in patients with these mutations.
Study Design:
We will study 32 Parkinson’s disease patients (16 with and 16 without GBA mutations). Patients will be tested for GBA mutations, clinically evaluated and undergo brain imaging with functional MRI and metabolic PET. Testing will be repeated 18 months later. Rates of clinical and network progression will be compared for carriers and non-carriers of GBA mutations.
Impact on 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. We will also determine whether MRI network methods, which are less invasive and more broadly available than PET, produce comparable network progression measurements in individual patients. These determinations will be critical for the design of clinical trials of new disease-modifying drugs.
Next Steps for Development:
The study will provide essential support for the use of network biomarkers (measured either with PET or MRI) in future disease-modification trials. In addition to gauging the efficacy of drugs/interventions targeting GBA pathways, network biomarkers may help customize therapy for individual patients.