Funded Studies
Objective/Rationale:
By incorporating our Spanish LRRK2 cohort with G2019S and R1441G mutations into the existing LRRK2 Cohort Consortium (L2CC) of people of Ashkenazi Jewish and North African Arab-Berber descent, we intend to gain accelerated understanding of the connection between mutations in the LRRK2 gene and PD. This collaborative approach with marked sharing philosophy will provide further insight into the genetic, clinical and biological picture of LRRK2-associated PD. In addition, the study of a genetically defined patient population will bring increased knowledge into possible biomarkers for early diagnosis and disease progression that may be useful not only for LRRK2-associated PD but also for the idiopathic form of the disease.
Project Description:
To investigate the earliest stages and mechanism of reduced penetrance in LRRK2-associated PD, we initiated this study. This project joins efforts of the Hospital Clínic of Barcelona (E. Tolosa) and the Hospital de Donostia of San Sebastian (J.F. Martí-Massó). For each of the G2019S and R1441G mutations, the expanded cohort consists of 100 PD patients carrying the mutation (manifesting carriers; MC), 50 aSymptoms & Side Effects first degree relatives with the mutation (non-manifesting carriers; NMC) and 50 aSymptoms & Side Effects first degree relatives without the mutation (non-manifesting non-carriers 1; NMNC-1). As a second control group, 50 healthy aSymptoms & Side Effects subjects without parkinsonism or family history of PD, without G2019S or R1441G, gender-, age-matched to the group of NMC are included (non-manifesting non-carriers 2; NMNC-2). Our sample encompasses, besides the common G2019S, the R1441G mutation that showed a founder effect in the Basque region. Detailed clinical data (non-motor symptoms; NMS), imaging data (DAT-SPECT, PET) and biological samples (blood, CSF, fibroblasts) of participating subjects will be part of the MJFF L2CC.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Progress in understanding the biology of LRRK2 might be instrumental for therapeutic development. Thus, our study could contribute to (i) elucidate the role of LRRK2 in the pathophysiology of PD; (ii) identify biological and imaging pre-motor markers in PD; (iii) detect pre-motor and early PD clinical biomarkers for PD diagnosis and progression; (iv) investigate which role lifestyle and environmental factors play influencing disease expression; (v) collect skin-derived tissues from the LRRK2 cohort to perform molecular studies on LRRK2 function and provide a PD cellular model for drug testing; (vi) develop proof-of-concept therapeutic tests.
Anticipated Outcome:
As anticipated outcome of the study together with the MJFF L2CC we aim to be able to (i) refine the clinical characterization of patients with LRRK2-associated PD; (ii) investigate the natural course of non-motor symptoms (NMS) and nigrostriatal involvement in the pre-motor phase of PD; (ii) collect clinical, imaging and biological data of NMC with the parental LRRK2 mutation to provide novel insights into disease mechanisms; (iv) identify genetic and environmental factors modifying the symptoms of disease expression including age-at-onset and parkinsonism severity.