Synopsis

Keywords: Neuro, White Matter, DTI , MTI

X-linked Pelizaeus Merzbacher disease is characterized by failure of myelin formation and subsequent axonal damage. Severity of disease courses varies depending on the underlying gene mutation. Eight male patients were recruited for the study. MR-imaging protocol included MTI, MWI for evaluation of myelin related parameters and DTI for assessment of axonal integrity. Decreased values in quantitative MTI and MWI parameter maps and ROI analyses indicated severe myelin deficit in all patients. However, FA reflected various degrees of axonal involvement among patients with deferent genotypes. Multimodal MRI can facilitate assessment of simultaneous disease processes in childhood hypomyelinating leukodystrophies.

Introduction

Pelizaeus Merzbacher Disease (PMD) is a X-linked childhood leukodystrophy (LD) characterized by failure of myelin formation. Several mutations in the proteolipid protein (PLP) gene have been identified as underlying causes. They give raise to different disease courses of varying severity, i.e. a duplication lead to classical forms with onset in infancy and symptoms like nystagmus, pronounced muscular hypotonia and developmental delay¹. All phenotypes share extensive signal hyperintens white matter (WM) on T2-weighted MRI. Over time, all patients also develop spasticity as the myelin deficit inevitably provokes axonal damage. Following the recommendations for hypomyelinating LD our MRI protocol included diffusion tensor imaging (DTI), magnetization transfer imaging (MTI) and multi-component relaxation derived from mcDESPOT ². Aims of this longitudinal quantitative MRI study were to investigate, i) if myelin pathology and axonal damage can be distinguished and assessed separately as two distinct pathogenetic processes, ii) if severity of disease courses is reflected in quantitative MRI parameters

Methods

A total of 8 male patients (age 2.5 – 37 yrs) with genetically confirmed PMD were included in this study. Disease course and gene mutations are displayed in Table 1. All patients underwent MRI studies using a 3 T scanner (Siemens Healthcare, Magnetom Tim Trio or Prisma Fit). Imaging protocol encompassed conventional T1- and T2-weighted sequences as well as DTI, MTI and multi-component relaxation derived from mcDESPOT with parameter settings as described before^3,4.

After correction for eddy current effects, fractional anisotropy (FA) maps were obtained from DTI images using the ‘dtifit’ function from FSL. Myelin water fraction (MWF) and MT saturation (MTsat) maps were quantified from mcDESPOT and MT images respectively by using inhouse developed Linux based tools3,4. For each patient FA, MTsat and MWF maps were registered to the respective T1-weighted image. Regions of interest (ROI) were placed manually on the FA maps in the splenium (SPL) and then superimposed to the coregistered MTsat and MWF maps. Mean FA, MTsat and MWF of the ROI were compared with control data.

Control data were selected from our local data base of neurologically asymptomatic children. The control group consisted of 34 subjects for MTI measurements and of 49 subjects for DTI studies with age range 0.2 – 18 years. Control values for MWF were taken from literature published by Deoni et al.⁵.

Table 1: Clinical data of the PMD patients
Pat Nr.	Pat-1	Pat-2	Pat-3	Pat-4	Pat-5	Pat-6	Pat-7	Pat-8
mutation	dupl.	point mut.	point mut.	point mut.	null mut.	dupl.	dupl.	point mut.
disease course	classic	intermediate-classic	intermediate-classic	severe connatal	mild PLP null syndrome	classic	classic	classic
no. of sessions	5	1	2	1	1	1	1	1
dupl.: duplication; mut.: mutation; no.: number

Results

Control data depicted normal myelination processes which slow down and level off at around 2.5 yrs of age as reflected in both myelin related parameters obtained from SPL MTsat and quantitative MWF (Figure 1). MTsat values (obtained in 8) and MWF values (available from 5) patients were significantly decreased. Pat-1 monitored over 8 yrs showed a mild increase of both values over time. FA values of Pat-1, 2, 3, 6 were in lower normal ranges or slightly decreased. Lowest FA in childhood was detected in Pat-4 with the most severe clinical course (connatal, Table 1). Interestingly, Pat-5 with the mildest phenotype (Table 1) also showed a distinctly decreased FA. Figure 2 displays hyperintense WM in the T2-weighted images of representative Pat-1 and 3 and in parallel the global myelin deficit reflected by low values in the MTsat and MWF maps compared to the control (bottom row).

Discussion

The uniformly lower value of myelin related parameters MTsat and MWF maps point to global hypomyelination in all patients characteristic for PMD and in line with the literature⁶. ROIs analyses were carried out in the highly parallel fibers of the SPL. The lowest FA values in the pediatric patients could be found in Pat-2 with the most severe conatal course which might reflect early involvement of axonal structures. Interestingly, also Pat-5 demonstrated particularly low FA although his mild clinical course being at the other end of a possible spectrum. However, in PLP null syndrome axonal damage including loss and degeneration has been described as the predominant pathology⁷.

Conclusion

In conclusion, FA, the DTI parameter analyzed, might reflect the extent of axonal involvement in the different clinical phenotypes facilitating the assessment of parallel disease processes in PMD. These phenotypes may be of utmost importance for potential therapeutic interventions. Subsequently, management of patients may need to be adjusted accordingly. In this ongoing study other DTI parameter will be included as well as brain volume measures and longitudinal data.

Acknowledgements

No acknowledgement found.