Summary

Eligibility
for people ages 18 years and up (full criteria)
Healthy Volunteers
healthy people welcome
Location
at UCSD
Dates
study started
estimated completion
Principal Investigator
by Irene Litvan, MD (ucsd)

Description

Summary

Rostock International Parkinson's Disease Study - An International, multicentre, epidemiological observational study aiming at identification of 1,500 LRRK2-positive patients, the identification of 1,500 non-LRRK2 PD patients and the establishment of a candidate biomarker in the LRRK2-positive cohort.

Official Title

Rostock International Parkinson's Disease Study: an International, Multicenter, Epidemiological Observational Study

Details

Parkinson's disease (PD) is one of the most common neurodegenerative disorders worldwide, affecting approximately 1% of individuals older than 60 years and causes progressive disability.

Clinical signs and symptoms of PD include the following: asymmetric tremor at rest, bradykinesia, muscle rigidity, postural instability, gait abnormalities including festination and freezing. Onset is typically after the age of 50 years and the disease is commonly slowly progressive. The most common initial finding of PD is a resting tremor in the upper extremity. Over time, participants experience progressive bradykinesia, rigidity, and gait difficulty, while the axial posture becomes progressively flexed. Non-motor symptoms are common in all stages of Parkinson disease and they include constipation, seborrhea, hyposmia or anosmia, sympathetic denervation of the heart, depression and/or apathy, sleep disturbances, cognitive decline and dementia. They may appear prior to the movement disorder and can be used as preclinical markers of PD.

PD is mostly considered as idiopathic disease; however more and more data suggest that it is a disease that involves interaction of genetic and environmental factors. The most common monogenic form and the one most closely resembling idiopathic PD is LRRK2 (Leucine-rich repeat kinase 2 gene) associated PD.

The most common monogenic form and the one most closely resembling idiopathic PD is LRRK2 (Leucine-rich repeat kinase 2 gene) associated PD. First identified in 2004, LRRK2 mutations are currently still the most commonly known cause of PD and account for up to ~40% of all Parkinson's disease cases in select populations. The majority of reported LRRK2-positive PD patients are Caucasian (63%), whereas all other ethnicities comprise ~10% or fewer patients of described mutation carriers despite clusters in the Ashkenazi Jewish and Arab Berber populations. With respect to country of origin, the majority of patients were re-ported to reside in Italy or Spain (14% each), Great Britain (10%) or Norway (9%). Definitely pathogenic variants identified in LRRK2 include p.G2019S, p.R1441C/G/H, p.N1437H, p.Y1699C, and, p.I2020T. Of these, the p.R1441G mutation is particularly frequent, as it represents a founder mutation in the Basque population where it is responsible for 46% of all familial PD. Very rarely, this mutation has also been observed in other populations where it arose on a different haplotype. LRRK2 p.Gly2019Ser mutation accounts for about 0.5% simplex cases and >5% familial cases in various ethnic groups worldwide. Furthermore, genome-wide association studies have identified common polymorphisms in LRRK2 that associate with idiopathic PD, implicating LRRK2 function in susceptibility to late-onset PD in individuals without pathogenic mutations.

LRRK2 mutations cause PD with age-related penetrance and clinical features identical to late-onset sporadic PD. Biochemical studies support an increase in Lrrk2 kinase activity and a decrease in GTPase activity for kinase domain and Roc-COR mutations, respectively. Strong evidence exists that Lrrk2 toxicity is kinase dependent, leading to extensive efforts to identify selective and brain-permeable Lrrk2 kinase inhibitors for clinical development. Lrrk2 kinase inhibition is currently one of the most prevailing disease-modifying therapeutic strategies for PD. Thus, Lrrk2 kinase inhibitors are in development as potential Parkinson's disease therapeutics.

Furthermore, there is now evidence showing that LRRK2 expression and phosphorylation levels have a potential as markers of Parkinson's disease. Recently, the presence of Lrrk2 was confirmed in exosomes from human biofluids, including urine and cerebrospinal fluid. Moreover, elevated LRRK2 autophosphorylation was identified in brain-derived and peripheral exosomes in LRRK2-mutation carriers. In summary, it has been shown that markers of Lrrk2 activity and function may be detected in human blood and that they are relevant for pathogenesis if PD.

Thus, the biochemical analyses of human blood from LRRK2 positive participants and LRRK2 negative participants create a strong base for the development of PD-related biomarkers. This biomarker may in turn be even more accessible than genetic testing and it may serve for diagnosis, prognosis, and prediction of PD.

Keywords

Parkinson´s Disease Biomarker LRRK2 GBA PD Genetics Parkinson Disease High risk population

Eligibility

You can join if…

Open to people ages 18 years and up

  • Informed consent is obtained from the participant.
  • The participant is equal to or older than 18 years old.
  • The participant is clinically diagnosed with Parkinson's disease
  • The participant is a family member of a participant with LRRK2 parkinsonism.
  • The participant is a member of a high risk population.

You CAN'T join if...

  • Inability to provide informed consent.
  • The participant is younger than 18 years old.
  • The participant is not suffering from Parkinson's disease.
  • The participant is not a family member of a participant with LRRK2 parkinsonism.
  • The participant is not a member of a high risk population.
  • Previously enrolled in the study.
  • Participant in custody.

Locations

  • University of California (UC) San Diego accepting new patients
    La Jolla California 92093 United States
  • Pharmacology Research Institute accepting new patients
    Newport Beach California 92660 United States
  • Neuro-Pain Medical Center accepting new patients
    Fresno California 93710 United States
  • Pharmacology Research Institute accepting new patients
    Encino California 91316 United States

Lead Scientist at UC Health

  • Irene Litvan, MD (ucsd)
    Professor, Neurosciences. Authored (or co-authored) 298 research publications.

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
Centogene AG Rostock
ID
NCT03866603
Study Type
Observational
Last Updated