GBA Pathway markers for Lewy body dementias (U01)

Clemens Scherzer
PI:
Clemens Scherzer, MD
Harvard University

Summary

An enzyme (beta-glucocerebrosidase, encoded by the GBA gene) controls the production of critical brain lipids (or fats), the sphingolipids, which are important for membranes and function of brain cells. Defects in this GBA pathway are connected to a build up of a protein (alpha-synuclein), which forms tiny spheres (Lewy bodies) that are scattered throughout the brain of a substantial number of people with memory loss (Lewy body dementia, short LBD). Drugs designed to correct this pathway are under development for clinical trials. A tool kit of tests is needed to accompany such drugs. Such tests should help to tell whether the new treatments are working.

In the first goal of this project, we will determine, whether this GBA pathway is abnormal in blood and cerebrospinal fluid (an accessible liquid surrounding the brain) of hundreds of individuals with Lewy body dementias, healthy people, and participants with other types of dementia. In the second goal, we will analyze, whether biomarkers (biological tests) for the GBA pathway can track disease progression in Lewy body dementias over time. Moreover, we will collect clinical data, cerebrospinal fluid, and blood samples of these patients and controls from Harvard-affiliated hospitals. We will share the patient samples and clinical data with scientists around the nation through the biorepository and website of the NIH NINDS PDBP.

This study is designed to translate clues from the GBA pathway into biomarkers for clinical drug trials for patients with Lewy bodies and memory loss. It will create a prototype tool kit of tests for innovative, genetics-inspired, biomarkers-guided phase II trials for this major cause of memory impairment.

Abstract

Dysfunction of the β-glucocerebrosidase gene (GBA) pathway is genetically, neuropathologically, and biochemically implicated in Lewy body dementias. GBA pathway-directed markers and treatments offer an opportunity for rapidly implementing proof-of-concept trials of drugs designed to slow disease progression. A tool kit of tests is needed for biomarkers-guided go/no-go decisions that includes molecular biomarkers for target engagement, drug response, and disease progression. In Aim 1, we will determine, whether disruption of the GBA pathway in plasma and cerebrospinal fluid is specifically associated with Lewy body dementias in a large, cross-sectional study of 435 individuals with Lewy body dementias, healthy controls, and disease controls with other dementias using targeted, quantitative mass spectrometry assays for fifty pathway sphingolipids and an assay for β-glucocerebrosidase activity. Moreover, we will explore whether quantitative or qualitative changes in the GBA pathway inform on GBA mutation status, clinical disease severity, and clinical diagnosis. In Aim 2, we will determine, whether GBA pathway markers longitudinally track disease progression in Lewy body dementias. In Aim 3, we will longitudinally collect clinical data, CSF, and blood samples of 100 patients with DLB, PDD and controls from Harvard-affiliated hospitals and expand the NINDS Parkinson's Disease Biomarkers Program collection. These analyses will translate genetic clues into clinical trials markers. They will create the tools needed for innovative, genetics-inspired, biomarkers-guided phase II trials for Lewy body dementias and generally enrich the PDBP resource. PUBLIC HEALTH RELEVANCE: Lewy body dementias are thought to account for up to 20% of all dementia cases. Dysfunction of the β- glucocerebrosidase gene (GBA) pathway is genetically, neuropathologically, and biochemically implicated in Lewy body dementias. GBA pathway-directed markers are needed to rapidly implement proof-of-concept trials of drugs designed to slow disease progression.

Goals

Goals of Project

  • Recruitment: We will enroll 75 new subjects with LBD for annual cognitive and biosample (blood and CSF) assessment.
  • Discovery:  We will use blood and CSF from patients with LBD and other neurodegenerative diseases that were previously enrolled in the Harvard Biomarker Study to screen for GBA pathway components that might be unique to LBD.
  • Discovery:  We will attempt to verify that the GBA pathway components we identified in the previously enrolled patients can also be found in the newly enrolled patients.
  • Discovery: We will develop a new assay to measures the progression of Lewy body dementias with greater precision and earlier in the disease process. This robust, mechanism-linked GBA pathway test may improve drug development and the treatment of LBD.
  • Resource Building: We will enrich the NINDS Parkinson’s Disease Biomarkers Program by contributing samples (CSF and blood) collected from patients with LBD over the course of the disease progression.

Enrollment Goals

  • 75 new subjects with Lewy Body Dementia (LBD)  (varying stages of disease)

Participate

To participate in this study, please contact one of the following:

Please contact:

Elena Abatzis
Clinical Coordinator
Brigham & Women's Hospital
Email
eabatzis@bwh.harvard.edu

Available Data Types

Mass-Spec: PDBP-STUDY0000242

Clemens Scherzer