Myelin imaging in amyotrophic and primary lateral sclerosis

Abstract

Primary lateral sclerosis (PLS) has been regarded as a rare, extreme form of amyotrophic lateral sclerosis (ALS). Like ALS, it is a clinical diagnosis without established biomarkers. We sought to explore loss of cerebral myelin in relation to clinical features, including cognitive impairment, in cases of both ALS and PLS. A novel MRI sequence (mcDESPOT) sensitive to water pools within myelin and intra- and extra-cellular spaces was applied to 23 ALS patients, seven PLS patients and 12 healthy controls, with interval follow-up in 15 ALS and four PLS patients. Results demonstrated that PLS patients were distinguished by widespread cerebral myelin water fraction reductions, independent of disease duration and clinical upper motor neuron burden. ALS patients showed a significant increase in intra- and extra-cellular water, indirectly linked to neuroinflammatory activity. Limited measures of cognitive impairment in the ALS group were associated with myelin changes within the anterior corpus callosum and frontal lobe projections. Longitudinal changes were only significant in the PLS group. In conclusion, in this exploratory study, myelin imaging has potential to distinguish PLS from ALS, and may have value as a marker of extramotor involvement. PLS may be a more active cerebral pathological process than its rate of clinical deterioration suggests.

Figure 1.

Reductions in MWF for PLS patients compared to healthy controls (A, significant reductions in orange with trends in blue), and PLS patients compared to ALS patients (B, significant reductions in red with trends in dark blue). Increases in IE-water T2 for PLS patients compared to healthy controls (C, non-significant trends in light blue) and ALS patients compared to healthy controls (D, significant increases in red-yellow with trends in green). All p-values corrected for multiple comparisons. Images displayed by radiological convention.

Figure 2.

Regional white matter tract correlations, notably including the anterior corpus callosum and frontal projections, between lower ACE scores and reduced MWF in ALS patients (A), and increased IE-water T2 in ALS patients (B). All p-values corrected for multiple comparisons. Images displayed by radiological convention.

Figure 3.

Regional white matter tract correlations, notably including anterior corpus callosum and frontal projections, between higher TMT B-A scores (reflecting dysexecutive function) and reduced MWF in the ALS group (A), in the ALS and PLS patients combined (B); IE-water T2 increases in ALS patients (C) and IE-water T2 increases in the combined group (D). All p-values corrected for multiple comparisons. Images displayed by radiological convention.

Figure 4.

Regional white matter tract correlations, with a notable involvement of frontal lobe projections, between reduced category fluency and decreased MWF in ALS patients (A), decreased MWF in all patients (B), increased IE-water T2 in ALS patients only (C), and increased IE-water T2 in all patients (D). All p-values corrected for multiple comparisons. Images displayed by radiological convention.