Thursday, April 3, 2025
4/3/2025
Non-Invasive Imaging of Neurological Glycogen Storage Disease - PROJECT SUMMARY/ABSTRACT Lafora disease (LD) is a fatal, autosomal recessive, neurodegenerative disorder that presents as epilepsy in late childhood or adolescence and is followed rapidly by cognitive deterioration, dementia, and death within 10 years of onset. Currently, there is no treatment and anti-seizure drugs are only beneficial in early stages. LD is characterized by the intracellular accumulation of glycogen-like aggregates called Lafora bodies (LBs) that occur in cells from most tissues, thus LD is also a glycogen storage disease (GSD). Although multiple labs are defining LD cellular and behavioral disease sequela as well as developing therapies, there is currently no biomarker to assess LD progression and/or treatment efficacy non-invasively. We recently reported a novel approach for imaging glycogen non-invasively using the nuclear Overhauser effect (NOE) between aliphatic and hydroxyl protons in glycogen that can be detected with standard MRI equipment. Using this glycoNOE approach, we successfully showed that changes in liver glycogen could be measured dynamically with high temporal and spatial resolution. Importantly, there was a linear correlation between glycoNOE contrast and glycogen concentration. The objective of this grant is to establish a quantitative MRI test for reporting LB load and treatment efficacy in muscle and brain non-invasively. To achieve this, we will utilize LD mice as our model system, and we have set the following specific aims (1a) Establish a robust glycoNOE MRI protocol for detecting LBs in skeletal muscle, (1b) Calibrate glycoNOE MRI in muscle as a function of concentration of glycogen, (2a) Develop a glycoNOE MRI-based quantitative test for reporting LBs in the brain, (2b) Longitudinal study of LD in mice using glycoNOE, (3a) Utilize glycoNOE MRI to monitor LB levels in LD mice after a therapeutic intervention, (3b) Assess the re-accumulation of LBs after treatment. These aims will result a non-invasive method for imaging glycogen changes in the brain and muscle with high spatial resolution. The methods developed in this proposal will be immediately translatable to standard human MRI scanners. This technology will be applicable to all glycogen storage diseases, which affect about 1 in 15,000 and thus expand the scope beyond LD. The proposed aims are critical to enable translation of these results into diagnosing and monitoring of treatments for LD and the broader GSD patient population.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).