Disease aggressiveness signatures of amyotrophic lateral sclerosis in white matter tracts revealed by the D50 disease progression model

Abstract

Numerous neuroimaging studies in amyotrophic lateral sclerosis (ALS) have reported links between structural changes and clinical data; however phenotypic and disease course heterogeneity have occluded robust associations. The present study used the novel D50 model, which distinguishes between disease accumulation and aggressiveness, to probe correlations with measures of diffusion tensor imaging (DTI). DTI scans of 145 ALS patients and 69 controls were analyzed using tract-based-spatial-statistics of fractional anisotropy (FA), mean-(MD), radial (RD), and axial diffusivity (AD) maps. Intergroup contrasts were calculated between patients and controls, and between ALS subgroups: based on (a) the individual disease covered (Phase I vs. II) or b) patients' disease aggressiveness (D50 value). Regression analyses were used to probe correlations with model-derived parameters. Case-control comparisons revealed widespread ALS-related white matter pathology with decreased FA and increased MD/RD. These affected pathways showed also correlations with the accumulated disease for increased MD/RD, driven by the subgroup of Phase I patients. No significant differences were noted between patients in Phase I and II for any of the contrasts. Patients with high disease aggressiveness (D50 < 30 months) displayed increased AD/MD in bifrontal and biparietal pathways, which was corroborated by significant voxel-wise regressions with D50. Application of the D50 model revealed associations between DTI measures and ALS pathology in Phase I, representing individual disease accumulation early in disease. Patients' overall disease aggressiveness correlated robustly with the extent of DTI changes. We recommend the D50 model for studies developing/validating neuroimaging or other biomarkers for ALS.

Patterns of grey and white matter changes differ between bulbar and limb onset amyotrophic lateral sclerosis

“…Disease severity was assessed with the revised ALS Functional Rating Scale (ALSFRS-R) ( Cedarbaum et al, 1999 ). For patients with ALS, the D50 model was applied to characterize the individual clinical disease course ( Poesen et al, 2017 , Prell et al, 2020 , Steinbach et al, 2020a , Steinbach et al, 2021 ), which is modelled based on all available ALSFRS-R scores. The derived D50 value depicts the overall disease aggressiveness, defined as the estimated time taken in months for a patient to lose 50% of his/her functionality.…”

“…For the Diffusion-Tensor-Images (DTI), 30 diffusion-weighted images (at b = 1000 s/mm 2 ) and 3 b = 0 images were acquired in a gradient-weighted spin-echo sequence using the following parameters: repetition time 7800 ms, echo time 97 ms, flip angle 90°, slice thickness 2.5 mm, pixel size 1.25 mm × 1.25 mm, acquisition matrix 96 × 96. The standardized pipeline for Tract–Based Spatial Statistics (TBSS) was applied using the FRMRIB Software Library (FSL, version 5.0) and resulted in normalized and skeletonized maps of Fractional Anisotropy (FA), Mean Diffusivity (MD), Axial Diffusivity (AD) and Radial Diffusivity (RD) (see also Steinbach et al (2021) ).…”

“…We therefore aimed to explore the neuroimaging patterns in b-ALS and l-ALS in a large cohort of well-characterized patients with normal cognitive performance. To take the high heterogeneity of patients’ individual disease course into account we applied the D50 progression model which provides distinct measures of disease aggressiveness and individual disease covered ( Poesen et al, 2017 , Prell et al, 2020 , Steinbach et al, 2020a , Steinbach et al, 2021 ). We hypothesized that this approach might overcome former obstacles of cross-sectional and longitudinal studies and thus help to unravel the neuroimaging correlates of the neurodegenerative burden in b-ALS.…”

Circulating miR-181 is a prognostic biomarker for amyotrophic lateral sclerosis

“…In addition, a modest but statistically significant correlation was found between plasma miR-181 levels and survival length from enrolment or onset (Figure S8C,D; Table S3). We further tested the D50 model-based descriptors, which is derivative of ALSFRS-R and addresses difficulties in characterizing aggression and the individual disease covered by traditional ALS clinical indices 24 . Applying D50 to miR-181 stratification revealed association of high miR-181 levels with aggressive disease (time taken to reach half functionality < 32 months), whereas low miR-181 levels are associated with moderate disease (time to half functionality > 57 months, p<0.001, Fig.…”

“…Correlation between the relative disease covered (rD50) in longitudinal plasma collections (X-axis) and levels of (A) miR-423-5p, (B) miR-484, (C) miR-92a-3p, and (D) miR-92b-3p. The relative D50 (rD50) is a derivative of ALS Functional Rating Scale-Revised (ALSFRS-R) decay that reveals the disease covered by individual patients independent of the rate of progression 24, 37 . For example, an rD50 of 0.0 signifies ALS onset, and 0.5 signifies the time-point where functionality is reduced by half.…”