Study Rationale:
Parkinson’s disease caused by genetic mutations in the gene called leucine rich repeat kinase 2 (LRRK2) is clinically indistinguishable from idiopathic Parkinson’s disease, in which the cause is unknown. However, pathological changes occurring in the brains of Parkinson’s patients with LRRK2 (known as LRRK2-PD) may differ and not be limited to deposits of clumps, or aggregates of the protein alpha-synuclein in brain cells, which play a central role in the development of Parkinson’s. Recently, a new test called real time quaking-induced conversion assay (RT-QuIC) has identified abnormal alpha-synuclein aggregates in the cerebrospinal fluid (CSF) of patients with idiopathic Parkinson’s. With the current study we aim to evaluate the aggregation of alpha-synuclein in CSF of patients with LRRK2-PD and in people without Parkinson’s symptoms who carry LRRK2 mutations using this novel and promising technique. Samples of idiopathic Parkinson’s patients and people without Parkinson’s will also be analyzed for comparative purposes.
Hypothesis:
We hypothesize that the detection of disease-causing alpha-synuclein aggregates in CSF of LRRK2-PD patients will show a lower proportion of positive cases compared to idiopathic Parkinson’s, reflecting the LRRK2-PD’s variable effects on the nervous system. We expect that in a reduced number of people without symptoms carrying LRRK2 mutations, alpha-synuclein RT-QuIC will be also positive, possibly identifying those at greater risk of eventually developing Parkinson’s.
Study Design:
We will conduct a study using alpha-synuclein RT-QuIC in CSF samples of LRRK2-PD (50 individuals), people without symptoms who have LRRK2 mutations (50 individuals), idiopathic Parkinson’s patients (50 individuals) and control volunteers without Parkinson’s (50 individuals) obtained from the LRRK2 Cohort Consortium biospecimen set. To validate the technique we will analyze the accuracy of alpha-synuclein RT-QuIC in brain tissue of people who have died: LRRK2-PD patients (six individuals), idiopathic Parkinson’s (six individuals) and control volunteers without Parkinson’s (six individuals). We will correlate the alpha-synuclein RT-QuIC results with the type of mutation and clinical characteristics of the patients to better understand the mechanisms related to the disease.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
In light of novel treatments targeting aggregated alpha-synuclein deposits and LRRK2-kinase inhibitors, it is crucial to define the presence of an ongoing aggregation of alpha-synuclein in LRRK2-PD patients. The results of this study will help direct targeted treatment strategies to LRRK2-PD patients and possibly improve early and precise diagnosis of Parkinson’s.
Next Steps for Development:
Longitudinal studies focused on detecting the occurrence of Parkinson’s among those people without symptoms carrying LRRK2 mutations will provide information on the predictive value of this test for the eventual development of Parkinson’s symptoms. This information is critical for the design and implementation of disease modification trials in the pre-diagnostic phase of LRRK2-PD.