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LRRK2 Activity and Markers of Parkinson's Disease in G2385R Carriers

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04349865
Recruitment Status : Recruiting
First Posted : April 16, 2020
Last Update Posted : April 16, 2020
Michael J. Fox Foundation for Parkinson's Research
Information provided by (Responsible Party):
Piu Chan, Xuanwu Hospital, Beijing

Brief Summary:

The goals of this study are

  1. To compare the functional effects of the LRRK2 G2385R variant among carriers with and without Parkinson's disease (PD) and non-carriers with and without PD
  2. To investigate the relationship between functional effects of the LRRK2 G2385R variant and PD associated phenotype
  3. To investigate the biomarkers associated with PD conversion in the LRRK2 G2385R variant carriers
  4. To compare the immune-related differences between PD patients/unaffected individuals with and without the LRRK2 G2385R mutation, and to investigate the effects of immune dysfunction on the clinical expression of PD

Condition or disease
Parkinson Disease

Detailed Description:

Pharmaceutical companies with LRRK2 kinase inhibitor programs are close to Phase 1 clinical testing. Phase II proof-of-concept clinical trials will need to be conducted in LRRK2 manifesting mutation carriers. This is currently a challenging task given the limited availability of this cohort.

While the LRRK2 G2019S mutation is the most common mutation present in Caucasians and certain ethic groups, the G2385R variant has been identified as a risk factor for sporadic PD in the Asian population (Chinese Han, Japanese and Korean). In fact, in these populations, the occurrence of this mutation is thought to be higher than (up to 4% of PD patients) the occurrence of the G2019S mutation in the Caucasian population. In contrast to G2019S, this variant has not been fully characterized. For example, there has been controversy regarding its kinase activity with some reporting higher and others lower activity. A systematic biochemical characterization of the G2385R is necessary to determine if this cohort may be useful in LRRK2 kinase inhibitor trials.

Although there were significant studies on the clinical characterization of LRRK2 risk variant carriers with or without PD, little is known which factor is more specific in predicting the conversion to PD and which biomarker can be used to measure the disease progression. Identifying these clinical phenotype and biomarkers will be critical for studying pharmaceuticals effective for PD.

Several lines of evidence point to a role of LRRK2 in the immune system. Particularly high LRRK2 expression has been discovered in macrophagic and monocytic cells, but not T-cells, leading to speculation of a functional role for LRRK2 in the innate immune system. LRRK2 is also expressed in toll-like receptor 4 (TLR-4)-activated microglia, brain-resident macrophage cells that have been implicated in the pathology of PD brain, and LRRK2 modulates proinflammatory responses in these cells via several immune signaling pathways. Moreover, enhanced neuroinflammation may contribute to neurodegeneration in PD patients carrying LRRK2 mutations. Further, recent genome-wide association studies highlight LRRK2 in the modification of susceptibility to the chronic autoimmune Crohn's disease and Mycobacterium leprae infection, raising the possibility that LRRK2 may contribute to PD through immunogenic mechanisms. Although neuroinflammation as a primary trigger or secondary process linked to PD remains unclear, the link between LRRK2 and the immune system provides an intriguing possibility for a potential pathogenic mechanism as well as aid in the identification of potential markers of LRRK2-related immune function that could inform therapeutic development and/or act as potential pharmacodynamic measures of LRRK2 activity.

This study will take advantage of the larger cohorts of LRRK2 G2385R variant carriers with or without PD established by the Chinese Parkinson Study Group in China.

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Study Type : Observational
Estimated Enrollment : 200 participants
Observational Model: Case-Control
Time Perspective: Cross-Sectional
Official Title: Assessment of LRRK2 Activity in G2385R Carriers and Markers Predicting Conversion to and Progression of Parkinson's Disease
Actual Study Start Date : May 22, 2018
Estimated Primary Completion Date : June 30, 2020
Estimated Study Completion Date : June 30, 2020

Resource links provided by the National Library of Medicine

Idiopathic PD
PD patients without the LRRK2 G2385R mutation
PD patients with the LRRK2 G2385R mutation
LRRK2 G2385R carriers
Subjects without PD who screen positive for the LRRK2 G2385R mutation
Subjects without PD who screen negative for the LRRK2 G2385R mutation

Primary Outcome Measures :
  1. LRRK2 activity [ Time Frame: baseline ]
    Differences of blood LRRK2 activity measured by the optimized laboratory protocols among LRRK2 G2385R carriers and non-carriers with or without PD

  2. Immune function [ Time Frame: baseline ]
    Immune-related differences between LRRK2 G2385R carriers and non-carriers with or without PD. Immunological measures include (a) distribution of peripheral blood lymphocyte populations: flow cytometry analysis for surface staining of CD19, CD22, CD79A, PAX5 on B cells, and CD11b, CD14, CD16 on monocytes; (b) cytokine profiles in serum: IL-6, IFN-γ, TGF-β, TNF-α; (c) flow cytometry analysis for proteins involved in several LRRK2-related immune signaling pathways: TLR-4, IFN-γ and TGF-β, NF-κB.

Secondary Outcome Measures :
  1. Clinical symptoms associated with blood LRRK2 activity [ Time Frame: baseline ]
    Non-motor and motor symptoms are measured using the following methods: Brief Smell Identification Test (B-SIT) , Hamilton Depression Rating Scale (HAM-D) , RBD Questionnaire-Hong Kong (RBDQ-HK), Mini-Mental State Examination (MMSE), Non-Motor Symptoms Scale for Parkinson's Disease (NMSS), MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Purdue Pegboard

Biospecimen Retention:   Samples With DNA
venous blood collected with EDTA anticoagulant

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   55 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

(1) PD patients are from the Chinese National Consortium of Parkinson Disease (CNCPD) cohort; meanwhile, new patients are enrolled from outpatient and inpatient departments.

2) Unaffected subjects are from a large population-based cohort (the Beijing Longitudinal Study of Aging).


Inclusion Criteria:

  1. PD patients:

    • A diagnosis of Parkinson's disease according to the 2015 MDS PD diagnostic criteria.
    • Willingness to take genetic testing.
  2. Unaffected subjects:

    • Individuals aged 55 years or older without a diagnosis of PD.
    • Willingness to take genetic testing.

Exclusion Criteria:

□ Clinically significant neurological disorders.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04349865

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Contact: Zhuqin Gu, MD, PhD 86-010-83198677

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Xuanwu Hospital of Capital Medical University Recruiting
Beijing, China
Contact: Zhuqin Gu, MD, PhD    86-010-83198677   
Principal Investigator: Piu Chan, MD, PhD         
Sponsors and Collaborators
Xuanwu Hospital, Beijing
Michael J. Fox Foundation for Parkinson's Research
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Principal Investigator: Piu Chan, MD, PhD Xuanwu Hospital of Capital Medical University
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Responsible Party: Piu Chan, Principal Investigator, Xuanwu Hospital, Beijing Identifier: NCT04349865    
Other Study ID Numbers: LRRK2G2385R
First Posted: April 16, 2020    Key Record Dates
Last Update Posted: April 16, 2020
Last Verified: January 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Piu Chan, Xuanwu Hospital, Beijing:
LRRK2 G2385R variant
Parkinson's disease
LRRK2 activity
Additional relevant MeSH terms:
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Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases