Brainstem–cortex disconnection in amyotrophic lateral sclerosis: bulbar impairment, genotype associations, asymptomatic changes and biomarker opportunities

Abstract

Background Bulbar dysfunction is a cardinal feature of ALS with important quality of life and management implications. The objective of this study is the longitudinal evaluation of a large panel imaging metrics pertaining to bulbar dysfunction, encompassing cortical measures, structural and functional cortico-medullary connectivity indices and brainstem metrics. Methods A standardised, multimodal imaging protocol was implemented with clinical and genetic profiling to systematically appraise the biomarker potential of specific metrics. A total of 198 patients with ALS and 108 healthy controls were included. Results Longitudinal analyses revealed progressive structural and functional disconnection between the motor cortex and the brainstem over time. Cortical thickness reduction was an early feature on cross-sectional analyses with limited further progression on longitudinal follow-up. Receiver operating characteristic analyses of the panel of MR metrics confirmed the discriminatory potential of bulbar imaging measures between patients and controls and area-under-the-curve values increased significantly on longitudinal follow-up. C9orf72 carriers exhibited lower brainstem volumes, lower cortico-medullary structural connectivity and faster cortical thinning. Sporadic patients without bulbar symptoms, already exhibit significant brainstem and cortico-medullary connectivity alterations. Discussion Our results indicate that ALS is associated with multi-level integrity change from cortex to brainstem. The demonstration of significant corticobulbar alterations in patients without bulbar symptoms confirms considerable presymptomatic disease burden in sporadic ALS. The systematic assessment of radiological measures in a single-centre academic study helps to appraise the diagnostic and monitoring utility of specific measures for future clinical and clinical trial applications.

Promises and pitfalls of imaging-based biomarkers in motor neuron diseases

“…The imaging studies of these 'early' PLS cohorts have revealed a pattern consistent with what is now called 'definite PLS' validating the utility of the new criteria [9,10]. Hereditary spastic paraparesis (HSP) has overlapping clinical features with PLS and the marked corticospinal, corpus callosum and, depending on genotype, cerebellar degeneration is also reminiscent of some of the radiological alterations observed in ALS [11,12,13 && ,14]. Low-incidence ALS mimics, such as postpolio syndrome, was traditionally associated with widespread cerebral disease, but recent imaging studies have highlighted the lack of atrophy both in supra-tentorial and infra-tentorial regions [15,16].…”

The involvement of language‐associated networks, tracts, and cortical regions in frontotemporal dementia and amyotrophic lateral sclerosis: Structural and functional alterations

“…This notion is supported by our findings of left hemispheric FC reduction between the endpoints of the frontal aslant track in cognitively unimpaired ALS patients, where traditional tractography did not detect white matter alterations. This demonstrates the benefit of evaluating a panel of structural and FC indices in motor neuron diseases as they may have divergent sensitivity to detect network degeneration (Abidi et al., 2021 , 2020 ; Meier et al., 2020 ; Tahedl, Tan, Chipika, et al., 2023 ; Tahedl, Tan, Shing, et al., 2023 ; Trojsi, Di Nardo, Caiazzo, et al., 2020 ). SC is typically appraised based on diffusion data sets, which have their own caveats particularly around regions of crossing fibers.…”

“…Our analyses highlight that focal structural changes alone do not account for clinical symptoms and instead of solely performing voxel‐wise analyses, the integrity of specific networks and tracts should be also evaluated (Bede, 2017 ; Tahedl, Tan, Chipika, et al., 2023 ). The shift from focality to circuitry has been repeatedly emphasized in ALS (Bak & Chandran, 2012 ; Bak et al., 2001 ; Grossman et al., 2008 ) and is consistent with the observation that specific neuropsychological functions are mediated by multisynaptic networks with distinct cortical and white matter components, many relayed through specific subcortical nuclei and sometimes modulated by cerebellar afferents (Bede et al., 2018 ; Bonelli & Cummings, 2007 ).…”