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Background <p>Amyotrophic Lateral Sclerosis (ALS) is a progressive neuromuscular disease with multifaceted phenotypic presentation thus obstructing objective disease staging. The D50 disease progression model is a framework to comprehensively dissect biomarker-signals towards their relevance regarding disease accumulation/phase (rD50), or disease aggressiveness (D50). Based on previous findings using 1.5-Tesla Magnetic-Resonance-Imaging (MRI), this study hypothesized that high-resolution MRI markers of Grey-Matter (GM) structural integrity would enable quantification of disease accumulation, independent of aggressiveness.</p> Methods <p>A separate cohort of 75 patients with ALS and 73 Healthy Controls (HC) underwent T1-weighted 3-Tesla MRI. Voxel-Based-Morphometry measured GM and White-Matter (WM) density and Surface-Based-Morphometry assessed Cortical Thickness (CT). Non-parametric Threshold-Free-Cluster-Enhancement with 5000 permutations was applied for inter-group and regression contrasts, whilst correcting for possibly interfering co-variates and applying Family-Wise-Error-adjustment.</p> Results <p>Compared with HC, the ALS cohort showed widespread decreases of CT and GM/WM density (<i>p</i> &lt; 0.001). These case–control effects were driven by patients scanned during rD50-defined disease Phase 2 (<i>p</i> &lt; 0.001). Within the ALS-cohort, direct Phase 2 versus Phase 1 contrasts revealed spatially-distributed decreases, reflecting higher disease accumulation (<i>p</i> &lt; 0.05). These were independent of disease aggressiveness (and onset-region), as corrected for in the models. Accordingly, all contrasts assessing aggressiveness did not yield significant results.</p> Conclusions <p>These semi-automated analyses of T1-weighted-images captured disease accumulation related GM structural integrity-loss in this cohort scanned with 3-Tesla MRI, independent of the underlying disease aggressiveness. This principle was validated across different scanners and field strengths, supporting its application for objective and non-invasive staging of patients with ALS, whereby true longitudinal studies are necessary.</p>

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Quantification of amyotrophic lateral sclerosis (ALS) disease accumulation with T1-weighted high-resolution magnetic resonance imaging: validation in an independent cohort

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月29日

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  • Philip Alexander Gremmler,
  • Janina von der Gablentz,
  • Julia Meyer,
  • Benjamin Ilse,
  • Behnaz Farahi Ghasraboonasr,
  • Sophie Dalbert,
  • Isabelle Jana Buchholz,
  • Julian Grosskreutz,
  • Robert Steinbach

摘要

Background

Amyotrophic Lateral Sclerosis (ALS) is a progressive neuromuscular disease with multifaceted phenotypic presentation thus obstructing objective disease staging. The D50 disease progression model is a framework to comprehensively dissect biomarker-signals towards their relevance regarding disease accumulation/phase (rD50), or disease aggressiveness (D50). Based on previous findings using 1.5-Tesla Magnetic-Resonance-Imaging (MRI), this study hypothesized that high-resolution MRI markers of Grey-Matter (GM) structural integrity would enable quantification of disease accumulation, independent of aggressiveness.

Methods

A separate cohort of 75 patients with ALS and 73 Healthy Controls (HC) underwent T1-weighted 3-Tesla MRI. Voxel-Based-Morphometry measured GM and White-Matter (WM) density and Surface-Based-Morphometry assessed Cortical Thickness (CT). Non-parametric Threshold-Free-Cluster-Enhancement with 5000 permutations was applied for inter-group and regression contrasts, whilst correcting for possibly interfering co-variates and applying Family-Wise-Error-adjustment.

Results

Compared with HC, the ALS cohort showed widespread decreases of CT and GM/WM density (p < 0.001). These case–control effects were driven by patients scanned during rD50-defined disease Phase 2 (p < 0.001). Within the ALS-cohort, direct Phase 2 versus Phase 1 contrasts revealed spatially-distributed decreases, reflecting higher disease accumulation (p < 0.05). These were independent of disease aggressiveness (and onset-region), as corrected for in the models. Accordingly, all contrasts assessing aggressiveness did not yield significant results.

Conclusions

These semi-automated analyses of T1-weighted-images captured disease accumulation related GM structural integrity-loss in this cohort scanned with 3-Tesla MRI, independent of the underlying disease aggressiveness. This principle was validated across different scanners and field strengths, supporting its application for objective and non-invasive staging of patients with ALS, whereby true longitudinal studies are necessary.