Objective/Rationale:
First, to study the effect of the presence of the LRRK2 G2019S mutation on brain activation patterns in Parkinson’s disease (PD) patients who recently converted into a diseased state by comparing carriers to non carriers using fMRI and DTI technology.
Second, to examine the relationships between the presence of the mutation and brain activation patterns among healthy first degree relatives of PD patients who carry the G2019S mutation in order to identify and characterize betweengroup differences which may serve as potential biological markers for sub-clinical diseased state.
Project Description:
A total of 100 healthy first degree relatives of LRRK2 G2019S positive PD patients as well as 10 PD patients will be enrolled to this study. Half of the subjects will carry the LRRK2 mutations and half will be non carriers. Subjects will undergo a 2.5 hour fMRI scan that will include both structural scans (DTI and SPGR) as well as functional scans during cognitive and motor scans (Stroop, N-Back, Rest, Domino, Motor Imagery and short movie clips). Each task is related to recognized impaired functions in PD patients (motor, cognition, affect and reward processing). Between-group differences will be analyzed and correlated to behavioral data collected.
Relevance to Diagnosis/Treatment of Parkinson’s disease:
The G2019S LRRK2 mutation is the most common genetic cause for PD. Healthy first degree relatives are a unique "at risk" population for the future development of PD. Utilizing fMRI technology should enable us to identify pre-motor neural differences in the carrier population which could be considered as compensatory mechanisms. Elucidating these mechanisms will assist in the understanding of PD progression and enable the development of new therapies that target the pre-motor phase of the disease.
Anticipated Outcome:
We propose that the combination of clinical, imaging and genetic testing obtained in this study will demonstrate significant differences between PD patients carriers of the LRRK2 mutation, healthy mutation carriers and controls, enabling the identification of high risk populations for developing PD as well as shedding light on the temporal dynamics of pre- motor PD.
Final Outcome
The aim of our study was to identify pre-motor differences in the carrier population utilizing the sensitivity of fMRI. Our protocol included tasks that were designed to assess different aspects that are known to be disrupted by PD such as motor, cognition, affect and reward in addition to connectivity and structural scans. Ninty-six individuals participated in this study out of which 94 were asymptomatic first degree relatives of patients with PD carrying the G2019S mutation in the LRRK2 gene. Differences in cerebral activations were observed between carriers and non-carriers of the mutation in both the motor and cognitive tasks. Carriers and non-carriers performed these tasks equally well but utilized different brain regions. Follow-up studies will enable us to better understand the meaning of these results, the natural development of disease and perhaps identify the transition phase from health to disease.