ABSTRACT Cervical spine abnormalities in mucopolysaccharidosis (MPS) may result in cervical spinal cord (CSC) compression and irreversible neurological disability. MRI signal intensity changes in CSC images occur in the presence of advanced stenosis, myelopathy, and developed clinical symptoms. The proposal presumes that deficits in CSC morphology and microstructure precede MRI signal changes and are predictive of clinical myelopathy. We will proceed with systematic validation comparing CSC morphology and microstructure in MPS patients and case-matched healthy controls. The overall objective is to analyze existing and acquired CSC MRI data and assess longitudinal CSC morphology and cross-sectional CSC microstructure in the MPS. The central hypothesis is that quantitative MRI is sensitive to CSC morphological and microstructural degeneration, myelopathy risk, and disease severity in MPS. To test the central hypothesis and, thereby, attain the overall objective, we will pursue two specific aims: Aim 1: Assess longitudinal morphological damage of CSC in MPS types I, II, and VI and Aim 2: Assess cross-sectional microstructural damage of CSC in MPS types I and VI. Aim 1 will test a working hypothesis that CSC morphology is altered due to cervical spinal compression and is predictive of myelopathy in MPS. Aim 2 will test a working hypothesis that CSC inner integrity is altered due to MPS I and VI diseases. We will demonstrate that quantitative CSC MRI measurements are proportional to myelopathy risk and disease severity in MPS. The effects of MPS treatment on CSC measurements will be investigated where possible. The proposal will identify candidates for biomarkers of myelopathy in MPS. Regarding the biomarker research, the proposal is a pilot preclinical exploratory phase 1. The project is innovative because it will: (i) discover the biomarker candidates of myelopathy risk and disease severity in MPS; (ii) diffusion tensor imaging (DTI) will be assessed in the CSC of MPS patients; (iii) demonstrate that DTI-based CSC microstructure can assess ongoing degenerative processes before visual and qualitative MRI signal intensity changes. Overall, the proposal aims to advance objective early myelopathy diagnosis, which can guide the timing of a prophylactic myelopathy treatment and improve clinical outcomes in MPS.