Myelin deterioration in Twitcher mice: motor evoked potentials and magnetic resonance imaging as in vivo monitoring tools

We have used magnetic resonance imaging (MRI) and
motor evoked potentials (MEPs) for monitoring disease
progression within the CNS of the Twitcher mouse, the
murine model for globoid cell leukodystrophy (GLD).
GLD is a lysosomal storage disorder, resulting from
galactocerebrosidase deficiency, causing central and
peripheral myelin impairment, leading to death, usually
during early infancy. Neuroradiological, electrophysiological,
and pathological parameters of myelin maturation
were evaluated in Twitcher mice between postnatal days
20 and 45. Healthy controls showed a gradual-appearance
MRI T2-weighted hypointensity of the corpus
callosum (CC) starting at about P30 and ending at about
P37, whereas MRI of age-matched Twitcher mice
showed a complete loss of the CC-related MRI signal.
MEPs allowed the functional assessment of myelin
maturation within corticospinal motor pathways and
showed a progressive deterioration of MEPs in Twitcher
mice with increased central conduction time (CCT; 5.12
6 0.49 msec at P27 to 6.45 6 1.96 msec at P32),
whereas physiological CCT shortening was found in
healthy controls (3.01 6 0.81 msec at P27 to 2.5 6 0.27
msec at P32). These findings were not paralleled by traditional
histological stainings. Optical observation of
Bielchowsky and Luxol fast blue-PAS stainings showed
mild axonal/myelin deterioration of the Twitcher brain
within this time frame. Our results demonstrate that serial
MRI and MEP readings are sensitive evaluation tools for
in vivo monitoring of dysmyelination in Twitcher mice and
underscore their potential use for longitudinal evaluation
of the therapeutic impact of gene and cell therapies on
these animals.