FV 948. Diffusion Tensor Imaging Parameters in Metachromatic Leukodystrophy: Biomarkers for Disease Progress and Therapeutically Therapeutic Evaluation

 

Background: Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disease, which leads to progressive demyelination. Children with the early-onset late-infantile form suffer from rapid neurological progression, whereas children with the later onset juvenile form have a more slowly progressing disease process. Hematopoiesis stem-cell transplantation (HSCT) is currently the only clinically available therapy. In patients with the juvenile form, in particular, we were able to reveal a positive outcome, if the transplantation was performed at an early disease stage.

While conventional magnetic resonance imaging (MRI) sequences display characteristic T2-hyperintensities in the cerebral white matter and are established useful for disease progression and prognosis after HSCT, diffusion tensor imaging (DTI) parameters might give more precise information, as they are able to describe microstructural processes, as the demyelination itself, more specifically.

Objective: Analysis of DTI parameters from transplanted and not-transplanted children with MLD during the course of the disease.

Research Question: Are DTI parameters at baseline (at diagnosis or before HSCT) predictive for the later disease course or outcome after HSCT?

Methods: In this study, 136 diffusion MRIs from children with late-infantile (n = 25, 2 transplanted) and juvenile (n = 37, 15 transplanted) MLD were analyzed retrospectively. One hundred eighty-eight diffusion MRIs from 119 healthy children (NIH-MRI study of normal brain development) were used as a control group. Three regions of interests (ROIs; frontal white matter, central region near the gyrus praecentralis (CR), and the posterior limb of the internal capsule were systematically marked by two raters and the mean diffusivity (ADC) and fractional anisotropy (FA) of fiber tracts were measured in those ROIs.

The disease process was retrospectively divided into slow and fast progressing to assess the predictive value of ADC and FA at an early stage (diagnosis) of MLD. For this distinction, the median time between first motor symptoms and loss of independent walking was used. The transplanted patients were graded according to their clinical outcome (stable vs. progressive) to analyze predictive values of baseline parameters.

Findings: In comparison to the healthy control group, children with MLD had decreased FA and increased ADC values in all analyzed regions both during the disease course and already at the time of diagnosis. Even in regions with normal appearing white matter in the conventional MRI sequences, ADC and FA values were already changed. While children with late-infantile MLD showed rapidly deteriorating DTI parameters in parallel with their clinical progression over a short time period, children with juvenile MLD showed a more variable course, still, with highly abnormal DTI parameters already at the time of first symptoms.

Not-transplanted juvenile patients with a rapid progressive disease course showed clearly increased ADC values in the CR (p < 0.01). The DTI parameters before and after HSCT were found to reflect the clinical disease course (stable vs. progredient).

Conclusion: DTI parameters can quantify and characterize the microstructural cerebral changes in MLD, may serve as surrogate parameters for the natural disease course, and allow prognostic statements. They may be useful for future indications for HSCT and its evaluation.