Evaluation of glucocerebrosidase pathway biomarkers in Parkinson's Disease (U01)

Title: Evaluation of glucocerebrosidase pathway biomarkers in Parkinson Disease (U01)

PI Name: Rachel Saunders-Pullman

URL: https://pdbp.ninds.nih.gov/study_profile/226

Repository: Parkinson's Disease Biomarker Program

Status: Controlled Access

Funding Source: NIH-NINDS

Abstract: Parkinson disease (PD) due to monoallelic glucocerebrosidase (GBA1) gene mutations (GBA-PD) is at the forefront of novel approaches to the treatment of PD. Exciting potential therapeutic agents that target the pathway disrupted in this genetic form of PD are becoming available, and evidence suggests that benefits extend to non-mutation PD, as well. Demonstration of effects in trials of potential disease-modifying agents for PD in general has been impeded by uncertainty about disease etiology, heterogeneity of underlying mechanisms, few identified targets, few sensitive and stable outcome measures, and insufficient surrogate markers. GBA1 mutations cause deficiency in the lysosomal glucocerebrosidase enzyme (GCase) and are the most common genetic factor associated with PD. This well-defined pathway allows study of a population with decreased heterogeneity of etiologic mechanism, and a known target for intervention. Evaluation of biochemical markers in this pathway in conjunction with clinical motor and non-motor features will provide outcome measures for clinical trials. Further, disruption of the GCase pathway may be an important representative mechanism for non-mutation, idiopathic PD (IPD), and has been implicated as a possible etiology in at least a subset of IPD. While our cross-sectional preliminary data is promising, validation and longitudinal assessment of these biomarkers are needed to optimize their utility in clinical trials. Unprecedented sharing of biospecimen and clinical data through the Parkinson?s Disease Biomarker Program (PDBP) enables us to leverage our extensive GBA cohort at Mount Sinai Beth Israel (MSBI). Using extant samples from our MSBI cohort, the Harvard Biomarker Study (HBS), and the PDBP, we propose to characterize focused biochemical measures of the GCase pathway, including central and peripheral biomarker assessments of enzyme, lipid and α-synuclein levels and their relation to clinical outcomes and decline. Specifically, we will: (Aim 1) validate findings in the MSBI dataset, associate peripheral and CSF markers, and assess their longitudinal change; (Aim 2) analytically derive a clinical severity score to optimally relate clinical and biological markers; (Aim 3) evaluate markers in IPD to discern whether a subset of IPD shares the same etiologic mechanism. Data submition Notes: Legacy data is submitted for subjects that have complete data/total scores (LD_EpworthSleepinessScale, LD_MOCA, LD_ModSchwabEnglandScale, and LD_UPDRS). UPDRS: If complete data is not available, motor scores (UPDRS-III) submitted when available. Values for UPDRS were rounded up for non-integer 0.5 increment ratings. For example, if item Part III: Motor Examination.UPDRSChaAriseScale was rated as 2.5, this would be rounded up to 3. Schwab and England: Ratings (Scale Score.UPDRStScaleSchEngDalLivScl ) were rounded down when scored in 0.5 increments. For example, a Schwab and England rating of 0.85 was rounded to 0.80. LD_FamilyHistory: Only family history of PD (variable: Parkinson's disease.FamHistMedclCondReltvTyp) was transferred, when known. Family history of PD was not collected on nieces, nephews, or cousins. Demographics: Education category (EduLvlUSATypPDBP ) was translated from MSBI to PDBP as follows (MSBI->PDBP), ("no formal education"->"Never attended/Kindergarten only"), ("1-8 (grade school)"->"8th Grade"), ("9-12 (high school)"->"High school graduate"), ("13-16 (college)"->"Bachelor's degree (e.g., BA, AB, BS, BBA)" )->("17-20+ (graduate of professional school, e.g. medical or law)"->"Doctoral degree (e.g., PhD, EdD)"). LD_VitalSigns: Data submitted for those with corresponding demographics. The date and time of all vital signs (Vital Signs.VitalSgnDateTime) were coded as being collected at noon of the day they were collected. For example, vital collection on June 12, 2015, was recorded as "2015-06-12T12:00:00.0".

Study ID: PDBP-STUDY0000226

Repository URL: https://pdbp.ninds.nih.gov/

Data Type: Clinical Assessment

Study Type: Natural History

Study Started On: 2015-09-01

Study Completed On: 2018-08-31

Estimated number of Subjects: 200