A prospective harmonized multicenter DTI study of cerebral white matter degeneration in ALS

Abstract

Objective: To evaluate progressive white matter (WM) degeneration in amyotrophic lateral sclerosis (ALS).

Methods: Sixty-six patients with ALS and 43 healthy controls were enrolled in a prospective, longitudinal, multicenter study in the Canadian ALS Neuroimaging Consortium (CALSNIC). Participants underwent a harmonized neuroimaging protocol across 4 centers that included diffusion tensor imaging (DTI) for assessment of WM integrity. Three visits were accompanied by clinical assessments of disability (ALS Functional Rating Scale-Revised [ALSFRS-R]) and upper motor neuron (UMN) function. Voxel-wise whole-brain and quantitative tract-wise DTI assessments were done at baseline and longitudinally. Correction for site variance incorporated data from healthy controls and from healthy volunteers who underwent the DTI protocol at each center.

Results: Patients with ALS had a mean progressive decline in fractional anisotropy (FA) of the corticospinal tract (CST) and frontal lobes. Tract-wise analysis revealed reduced FA in the CST, corticopontine/corticorubral tract, and corticostriatal tract. CST FA correlated with UMN function, and frontal lobe FA correlated with the ALSFRS-R score. A progressive decline in CST FA correlated with a decline in the ALSFRS-R score and worsening UMN signs. Patients with fast vs slow progression had a greater reduction in FA of the CST and upper frontal lobe.

Conclusions: Progressive WM degeneration in ALS is most prominent in the CST and frontal lobes and, to a lesser degree, in the corticopontine/corticorubral tracts and corticostriatal pathways. With the use of a harmonized imaging protocol and incorporation of analytic methods to address site-related variances, this study is an important milestone toward developing DTI biomarkers for cerebral degeneration in ALS.

Clinicaltrialsgov identifier: NCT02405182.

© 2020 American Academy of Neurology.

Figures

Figure 1. Whole-brain-based spatial statistics for cross-sectional comparison of FA maps of patients with ALS vs controls

This figure shows slice-wise and projectional views of cross-sectional differences in baseline fractional anisotropy (FA) in 66 patients with amyotrophic lateral sclerosis (ALS) vs 43 controls. Major significant alterations are localized along the corticospinal tract (CST) and in the frontal lobes. Representative slices demonstrate the main voxel clusters of results for the cluster along the CST (top left), in the brainstem (top right), and in the frontal lobe (bottom left). A projectional overlay reveals all clusters in a pseudo-3D view (bottom right). Significance level is coded according to the color bar. Corrections for multiple comparisons were made with the false discovery rate at p < 0.05 and a cluster-size approach. MNI = Montreal Neurological Institute.

Figure 2. Cross-sectional comparison of FA values in ALS-related tracts by tract-wise FA statistics

This figure shows the differences in mean fractional anisotropy (FA) values of different tracts at baseline in 66 patients with ALS compared to 43 controls. Tracts of interest were defined according to the sequential white matter tract involvement in agreement with the neuropathologic staging pattern in amyotrophic lateral sclerosis (ALS): the corticospinal tract (CST; stage 1), corticorubral and corticopontine tracts (stage 2), corticostriatal pathway (stage 3), and proximal portion of the perforant path (stage 4). The optical tract was used as a reference tract. Mean FA was significantly reduced in patients with ALS in the CST, corticopontine/corticorubral tracts, corticostriatal pathway, and the grand average of all tracts, and the perforant path showed a trend toward reduced FA. Values are given as differences between mean FA values of controls and mean values of patients with ALS (Δmean FA); error bars are given as SEM. *p < 0.05, **p < 0.005, corrected for multiple comparisons.

Figure 3. Whole-brain-based spatial statistics for the longitudinal comparison of FA maps in patients with ALS vs controls

(A) Slice-wise representations of significant longitudinal alterations (decline) of fractional anisotropy (FA) in 46 patients with amyotrophic lateral sclerosis (ALS) vs 34 controls. Major significant alterations are localized along the upper corticospinal tract (top left) and in the frontal lobes (top right). Significance level is coded according to the color bar. Corrections for multiple comparisons were made with the false discovery rate at p < 0.05 and a cluster-size approach. (B) The correlation of ΔFA per day with the slope of ALS Functional Rating Scale–Revised (ALSFRS-R) score in a results cluster localized in the upper corticospinal tract (CST). Mean (ΔFA)/d is the mean FA alteration per day. MNI = Montreal Neurological Institute.

Figure 4. Longitudinal comparison of FA values in ALS-related tracts by tract-wise FA statistics

This figure shows the longitudinal fractional anisotropy (FA) change (ΔFA/d is the slope of FA decrease in units per day) between baseline and 1 follow-up scan in 46 patients with amyotrophic lateral sclerosis (ALS) vs 34 controls. Tracts of interest were defined according to the sequential white matter tract involvement in agreement with the neuropathologic staging pattern in ALS: the corticospinal tract (stage 1), corticorubral and corticopontine tracts (stage 2), corticostriatal pathway (stage 3), and proximal portion of the perforant path (stage 4). The optical tract was used as a reference tract. Values are given as differences between mean difference FA values of ALS and mean difference values of controls; error bars are given as SEM.

Figure 5. Cross-sectional voxel-wise correlation of FA maps of patients with ALS with clinical scores

This figure shows slice-wise and projectional views of cross-sectional correlations of fractional anisotropy (FA) in the 66 patients with amyotrophic lateral sclerosis (ALS) with ALS Functional Rating Scale–Revised (ALSFRS-R) score (top row), finger-tapping-score (center row), and upper motor neuron (UMN) score (bottom row). Main clusters are demonstrated at the level of the center (left and central column, with Montreal Neurologic Institute [MNI] coordinates of the peak voxel). ALSFRS-R score shows correlation with FA values in the corticorubral tract and in the prefrontal lobes; finger-tapping shows correlation with FA values in the corticopontine tract; and UMN score shows correlation with FA values in the lower corticospinal tract (CST). The right column is a projectional overlay of all clusters in a pseudo-3D view. Significance level is coded according to the color bar: hot colors represent positive correlation; cold colors represent negative correlation. Corrections for multiple comparisons were made with the false discovery rate at p < 0.05 and a cluster-size approach.

Figure 6. Whole-brain-based spatial statistics for cross-sectional comparison of FA maps in fast vs slow ALS progressors

This figure shows slice-wise and projectional views of the cross-sectional voxel-wise comparison of fractional anisotropy (FA) in 28 fast amyotrophic lateral sclerosis (ALS) progressors vs 38 slow ALS progressors. Major alterations are localized along the corticospinal tract (CST). Significance level is coded according to the color bar. Corrections for multiple comparisons were made with the false discovery rate at p < 0.05 and a cluster-size approach. MNI = Montreal Neurological Institute.