Multimodal longitudinal study of structural brain involvement in amyotrophic lateral sclerosis

Abstract

ObjectiveTo understand the progressive nature of amyotrophic lateral sclerosis (ALS) by investigating differential brain patterns of gray and white matter involvement in clinically or genetically defined subgroups of patients using cross-sectional, longitudinal, and multimodal MRI.MethodsWe assessed cortical thickness, subcortical volumes, and white matter connectivity from T1-weighted and diffusion-weighted MRI in 292 patients with ALS (follow-up: n = 150) and 156 controls (follow-up: n = 72). Linear mixed-effects models were used to assess changes in structural brain measurements over time in patients compared to controls.ResultsPatients with a C9orf72 mutation (n = 24) showed widespread gray and white matter involvement at baseline, and extensive loss of white matter integrity in the connectome over time. In C9orf72-negative patients, we detected cortical thinning of motor and frontotemporal regions, and loss of white matter integrity of connections linked to the motor cortex. Patients with spinal onset displayed widespread white matter involvement at baseline and gray matter atrophy over time, whereas patients with bulbar onset started out with prominent gray matter involvement. Patients with unaffected cognition or behavior displayed predominantly motor system involvement, while widespread cerebral changes, including frontotemporal regions with progressive white matter involvement over time, were associated with impaired behavior or cognition. Progressive loss of gray and white matter integrity typically occurred in patients with shorter disease durations (<13 months), independent of progression rate.ConclusionsHeterogeneity of phenotype and C9orf72 genotype relates to distinct patterns of cerebral degeneration. We demonstrate that imaging studies have the potential to monitor disease progression and early intervention may be required to limit cerebral degeneration.

Longitudinal clinical and neuroanatomical correlates of memory impairment in motor neuron disease

“…A TDP-43 staging system reports the anteromedial areas of the temporal lobe to be affected in stage 4 in patients with ALS ( Brettschneider et al, 2013 ), in contrast to Tau pathology, which is more likely to affect the posterior parts of the MTL ( Llado et al, 2018 ). Along this line, it should be the entorhinal cortex that is more affected by disease pathology as opposed to the PhG, which, surprisingly, did not show any MND-related thinning at all, neither in this study nor in other studies investigating cortical thinning over time ( van der Burgh et al, 2020 ). This problem can only be fully addressed once TDP-43 PET tracers are available for clinical use.…”

Tackling clinical heterogeneity across the amyotrophic lateral sclerosis–frontotemporal dementia spectrum using a transdiagnostic approach

“… 61 , 62 While exploratory analysis could not be conducted in the ALS group due to the small sample size, past studies suggest that C9orf72 negative cases tend to show atrophy involving cortical frontal and temporal regions, while C9orf72 ALS cases tend to show more subcortical involvement of the thalamus, caudate, putamen and pallidum. 63 Future studies with a larger sample size of carriers of the C9orf72 expansions will prove useful in validating the current findings and further differentiating C9orf72 positive versus negative cases across the whole ALS–FTD spectrum.…”

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

“…Other neuroimaging studies (e.g. measuring cortical thinning) per se also suggested that b-ALS patients are specifically characterized by an early and widespread involvement of cerebral GM ( Schuster et al, 2013 , van der Burgh et al, 2020 ). In our study, especially cortical regions of the frontal and temporal lobes were widely affected and consistently corresponded with adjacent WM density decreases.…”