Structural imaging differences and longitudinal changes in primary lateral sclerosis and amyotrophic lateral sclerosis

Abstract

Magnetic resonance imaging measures have been proposed as objective markers to study upper motor neuron loss in motor neuron disorders. Cross-sectional studies have identified imaging differences between groups of healthy controls and patients with amyotrophic lateral sclerosis (ALS) or primary lateral sclerosis (PLS) that correlate with disease severity, but it is not known whether imaging measures change as disease progresses. Additionally, whether imaging measures change in a similar fashion with disease progression in PLS and ALS is unclear. To address these questions, clinical and imaging evaluations were first carried out in a prospective cross-sectional study of 23 ALS and 22 PLS patients with similar motor impairment and 19 age-matched healthy controls. Clinical evaluations consisted of a neurological examination, the ALS Functional rating scale-revised, and measures of finger tapping, gait, and timed speech. Age and ALSFRS score were not different, but PLS patients had longer duration of symptoms. Imaging measures examined were cortical thickness, regional brain volumes, and diffusion tensor imaging of the corticospinal tract and callosum. Imaging measures that differed from controls in a cross-sectional vertex-wise analysis were used as regions of interest for longitudinal analysis, which was carried out in 9 of the ALS patients (interval 1.26 ± 0.72 years) and 12 PLS patients (interval 2.08 ± 0.93 years). In the cross-sectional study both groups had areas of cortical thinning, which was more extensive in motor regions in PLS patients. At follow-up, clinical measures declined more in ALS than PLS patients. Cortical thinning and grey matter volume loss of the precentral gyri progressed over the follow-up interval. Fractional anisotropy of the corticospinal tracts remained stable, but the cross-sectional area declined in ALS patients. Changes in clinical measures correlated with changes in precentral cortical thickness and grey matter volume. The rate of cortical thinning was greater in ALS patients with shorter disease durations, suggesting that thickness decreases in a non-linear fashion. Thus, cortical thickness changes are a potential imaging marker for disease progression in individual patients, but the magnitude of change likely depends on disease duration and progression rate. Differences between PLS and ALS patients in the magnitude of thinning in cross-sectional studies are likely to reflect longer disease duration. We conclude that there is an evolution of structural imaging changes with disease progression in motor neuron disorders. Some changes, such as diffusion properties of the corticospinal tract, occur early while cortical thinning and volume loss occur later.

Keywords: ALS, amyotrophic lateral sclerosis; ALSFRS-R, ALS functional rating scale, revised; CC, corpus callosum; CST, corticospinal tract; Cortical thickness; DTI, diffusion tensor imaging; Diffusion tensor imaging; FA, fractional anisotropy; FreeSurfer; Longitudinal studies; MD, mean diffusivity; MRI, magnetic resonance imaging; Motor neuron disease; PLS, primary lateral sclerosis; UMN, upper motor neuron.

Supplementary Fig. 1

Lack of longitudinal changes in diffusion tensor fiber tracking measures of the corticospinal tract in patients with ALS (red squares) and PLS (blue circles). Values for the fractional anisotropy (A, B) and mean diffusivity (C, D) for individual patients at each time point are connected by solid lines. Time is referenced to the onset of each patient's symptoms. Dotted lines indicate 2 standard deviations above and below the mean of control values. Although the CST FA of patients is in the lower range of control values, and MD is in the higher range, there is no consistent pattern of change between the two time points.

Supplementary Fig. 2

Lack of longitudinal changes in diffusion measures for regions of the corticospinal tract defined by an atlas-based method (Oishi et al., 2009). (A) Fractional anisotropy of the corticospinal tract at the level of the pons, peduncle, internal capsule, corona radiata, and precentral subcortical white matter. (B) Mean diffusivity of the corticospinal tract at the same levels. The group means and SDs are noted for the left (L) and right (R) corticospinal tract at each level. Solid dark bars represent measures at the first evaluation, and lighter bars represent measures at the follow-up evaluation.

Fig. 1

Regions of the corticospinal tract defined by an atlas-based method that were used for longitudinal analysis of diffusion tensor imaging. Labeled regions include the pons (CST, blue), cerebral peduncle (Peduncle, turquoise), posterior limb of the internal capsule (PLIC, green), superior corona radiata (SCR, yellow), and the subcortical pre-central white matter (PreCG, red) (Oishi et al., 2009).

Fig. 2

Areas of cortical thinning identified in the cross-sectional study by a whole-brain vertex-wise analysis, shown projected on a smoothed average of all brains in this study. (FreeSurfer QDEC) Regions of thinning compared to healthy controls are shown for (A) ALS patients and (B) PLS patients. The color of the scale bar indicates the statistical significance of the cluster, ranging from the threshold value of p < 0.001 to p < 0.00001. White lines indicate the approximate region parcellated as precentral gyrus and the yellow lines indicate the region parcellated as paracentral region. Hemispheres are viewed from left to right as: left lateral, left medial, right medial, right lateral.

Fig. 3

Longitudinal changes in the cross-sectional area of the corticospinal tract. Dashed lines indicate the initial scan visit and solid colored lines indicate the follow-up. Fiber tracking was used to define the CST from the level of the mid-pons to the motor cortex and the two sides were averaged for the profiles. (A) In ALS patients, the cross-sectional area of the CST declined between the initial and follow-up evaluation. (B) In PLS patients, the CST cross-sectional area is smaller than in ALS, but there is no change during the follow-up interval. Dashed lines from left to right indicate three anatomic levels of the corticospinal tract: peduncle, internal capsule, and subcortical white matter.

Fig. 4

Differences in rates of cortical thinning as a function of disease duration in PLS and ALS patients in a whole-brain vertex-wise analysis. (A) Regions where the average rate of change in thickness differs between ALS patients and PLS patients are shown on the smoothed average brain template (FreeSurfer QDEC). The color of the scale bar indicates the statistical significance of the cluster, ranging from the threshold value of p < 0.001 to p < 0.00001. Hemispheres are viewed from left to right as: left lateral, left medial, right medial, right lateral. (B) Plots show the relationship between the rate of change in thickness (mm/year) for ALS patients (red squares) and PLS patients (blue circles) and the time of symptom onset (disease duration at the mid-point of the interval between scans). Data from each plot corresponds to the region of significance that is circled in the brain image directly above in (A). ALS patients (red dashed lines) had a faster average rate of thinning for the circled region compared to PLS patients (blue dashed lines). The solid lines show the fitted slopes for each disease group. Rate of change in thickness (mm/years) = (thickness2 − thickness1) / (time2 − time1).

Fig. 5

Longitudinal changes in the mean cortical thickness of the precentral gyrus in patients with ALS (red squares) and PLS (blue circles). Time is referenced to the onset of the patient's symptoms. (A) Left precentral gyrus. (B) Right precentral gyrus.