Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2024:43:103633.
doi: 10.1016/j.nicl.2024.103633. Epub 2024 Jun 14.

Temporal and spatial progression of microstructural cerebral degeneration in ALS: A multicentre longitudinal diffusion tensor imaging study

Affiliations
Multicenter Study

Temporal and spatial progression of microstructural cerebral degeneration in ALS: A multicentre longitudinal diffusion tensor imaging study

Hans-Peter Müller et al. Neuroimage Clin. 2024.

Abstract

Objective: The corticospinal tract (CST) reveals progressive microstructural alterations in ALS measurable by DTI. The aim of this study was to evaluate fractional anisotropy (FA) along the CST as a longitudinal marker of disease progression in ALS.

Methods: The study cohort consisted of 114 patients with ALS and 110 healthy controls from the second prospective, longitudinal, multicentre study of the Canadian ALS Neuroimaging Consortium (CALSNIC-2). DTI and clinical data from a harmonized protocol across 7 centres were collected. Thirty-nine ALS patients and 61 controls completed baseline and two follow-up visits and were included for longitudinal analyses. Whole brain-based spatial statistics and hypothesis-guided tract-of-interest analyses were performed for cross-sectional and longitudinal analyses.

Results: FA was reduced at baseline and longitudinally in the CST, mid-corpus callosum (CC), frontal lobe, and other ALS-related tracts, with alterations most evident in the CST and mid-CC. CST and pontine FA correlated with functional impairment (ALSFRS-R), upper motor neuron function, and clinical disease progression rate. Reduction in FA was largely located in the upper CST; however, the longitudinal decline was greatest in the lower CST. Effect sizes were dependent on region, resulting in study group sizes between 17 and 31 per group over a 9-month interval. Cross-sectional effect sizes were maximal in the upper CST; whereas, longitudinal effect sizes were maximal in mid-callosal tracts.

Conclusions: Progressive microstructural alterations in ALS are most prominent in the CST and CC. DTI can provide a biomarker of cerebral degeneration in ALS, with longitudinal changes in white matter demonstrable over a reasonable observation period, with a feasible number of participants, and within a multicentre framework.

Keywords: Amyotrophic Lateral Sclerosis; DTI; Diffusion tensor imaging; MRI; Magnetic resonance imaging; Motor cortex; Multicentre study.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Cross-sectional comparison of FA by whole brain-based spatial statistics (WBSS) and tractwise fractional anisotropy statistics (TFAS). (A) WBSS of FA maps. This figure shows slice-wise views of cross-sectional differences in baseline FA in 114 ALS patients compared to 110 controls; the major significant alterations in representative slices demonstrate clusters indicating reduced FA along the CST (top left), in the pons (top right), in the frontal lobe (bottom left), in the perforant path (bottom right), and corpus callosum (top left and bottom right). Significance level is coded according to the color bar. Corrections for multiple comparisons were made using the false discovery rate (FDR) at p < 0.05 and a cluster-size approach. (B) TFAS of FA-values in ALS-related tracts. This figure shows the differences in < FA > values of different tracts at baseline in 114 ALS patients compared to 110 controls. Tracts of interest (TOIs) were defined according to the sequential WM tract involvement in agreement with the neuropathological staging pattern in ALS: the corticospinal tract (CST – stage 1), the corticorubral and corticopontine tracts (c. pontine/c. rubral – stage 2), the corticostriatal pathway (c. striatal – stage 3), and the proximal portion of the perforant path (perf. path – stage 4), callosal tracts for CC areas I – V (see also projectional views). < FA > was significantly reduced in ALS patients in the CST, corticopontine / corticorubral tracts, corticostriatal pathway, proximal portion of the perforant path, and in tracts of callosal areas II and III. Subdivision of the CST into a lower and an upper part showed that the main alterations at baseline were located in the upper CST (see also projectional views). Values are given as differences of FA between controls and ALS patients (Δ<FA > ); percentages are given as the proportion of change from baseline < FA > of controls; error bars are given as standard error of the mean. * p < 0.05, ** p < 0.005, corrected for multiple comparisons.
Fig. 2
Fig. 2
Associations of FA to clinical scores. (A) Whole-brain-based spatial statistics (WBSS) for cross-sectional comparison of FA maps of faster vs. slower progressing ALS patients. This figure shows a projectional overlay of all clusters in a pseudo 3-D view of cross-sectional differences in baseline FA. The major significant alterations (decreased FA in faster progressors compared to slower progressors) are localized along the lower CST and in area III of the corpus callosum. (B-D) Cross-sectional voxelwise correlation of FA maps of 114 ALS patients with clinical scores at baseline. This figure shows projectional views of cross-sectional correlations of FA in ALS patients with ALSFRS-R score (B), clinical disease progression rate (decrease of ALSFRS-R per month) (C), and upper motor neuron (UMN) score (D). ALSFRS-R score and decrease of ALSFRS-R show correlation with FA values along the corticospinal tract (CST) and in the pons; UMN score shows correlation with FA values along the CST. Significance level is coded according to the color bar. Corrections for multiple comparisons were made using the false discovery rate (FDR) at p < 0.05 and a cluster-size approach.The projectional views are the summative overlay of all clusters in the respective direction.
Fig. 3
Fig. 3
Longitudinal comparison of FA by whole brain-based spatial statistics (WBSS) and tractwise fractional anisotropy statistics (TFAS). (A) WBSS of FA maps of 39 ALS patients vs. 110 controls. This figure shows projectional overlay of all clusters in a pseudo 3-D view of differences in FA at baseline, follow-up 1 (4.6 months), and follow-up 2 (9.2 months). At baseline, the major significant alterations are localized in the upper CST whereas in follow up 1 and follow up 2 the lower CST becomes more and more involved in the alteration pattern leading to an increased number of significantly altered voxels. Significance level is coded according to the color bar. Corrections for multiple comparisons were made using the false discovery rate (FDR) at p < 0.05 and a cluster-size approach. (B) TFAS of FA in ALS-related tracts. This figure shows the comparison of mean FA ( ) longitudinally; the x-axis is drawn to scale such that the three ALS time-points represent the mean time of each measurement spaced relative to each other and to the mean estimated disease onset (aligned to the controls at t = 0) in 39 ALS patients who completed all 3 visits compared to 110 controls (dashed lines). The point at x = 0 is the value of controls which is an estimate of the mean disease onset at t = 0, as introduced by Cardenas-Blanco and colleagues (Cardenas-Blanco et al., 2016). Tracts of interest (TOIs) were defined according to the WM tract involvement of the neuropathological staging pattern in ALS (upper panel) and in the callosal areas I – V (central panel). The upper part of the CST (lower panel) shows a higher < FA > reduction compared to the lower part as well as compared to the entire CST (upper panel). Values are given as differences between < FA > of ALS patients and < FA > of controls (Δ ); error bars are given as standard error of the mean. * p < 0.05, ** p < 0.005, corrected for multiple comparisons. BL – baseline, FUP – follow-up, c. pontine – corticopontine tract, c. rubral – corticorubral tract, c. striatal – corticostriatal pathway, perf. path – proximal portion of the perforant pathway.
Fig. 4
Fig. 4
Sample size calculations. Theoretical curves, set up from effect size and sample size calculation for FA values. (A) Sample size estimates per group for cross-sectional comparisons of ALS patients vs controls in callosal tracts of area III (“horseshoe” pattern) (Table 3B). (B) Sample size estimates per group for cross-sectional comparisons of ALS patients vs controls (Table 3C) in the upper part of the CST. (C) Sample size estimates for longitudinal comparison of baseline and follow-ups of ALS patients (Table 3D) in callosal tracts of area III.

References

    1. Agosta F., Rocca M.A., Valsasina P., et al. A longitudinal diffusion tensor MRI study of the cervical cord and brain in amyotrophic lateral sclerosis patients. J. Neurol. Neurosurg. Psychiatry. 2009;80:53–55. - PubMed
    1. Agosta F., Pagani E., Petrolini M., et al. Assessment of white matter tract damage in patients with amyotrophic lateral sclerosis: a diffusion tensor MR imaging tractography study. AJNR Am. J. Neuroradiol. 2010;31:1457–1461. - PMC - PubMed
    1. Arnold G., Boone K.B., Lu P., et al. Sensitivity and specificity of finger tapping test scores for the detection of suspect effort. Clin. Neuropsychol. 2005;19:105–120. - PubMed
    1. Behler A., Kassubek J., Müller H.-P. Age-related alterations in DTI metrics in the human brain – consequences for age correction. Front. Aging Neurosci. 2021;13 - PMC - PubMed
    1. Behler A., Lulé D., Ludolph A.C., Kassubek J., Müller H.P. Longitudinal monitoring of amyotrophic lateral sclerosis by diffusion tensor imaging: Power calculations for group studies. Front. Neurosci. 2022;16 - PMC - PubMed

Publication types