Progressive Cerebrocerebellar Uncoupling in Sporadic and Genetic Forms of Amyotrophic Lateral Sclerosis
Abstract
Background and Objectives
Amyotrophic lateral sclerosis (ALS) is predominantly associated with motor cortex, corticospinal tract (CST), brainstem, and spinal cord degeneration, and cerebellar involvement is much less well characterized. However, some of the cardinal clinical features of ALS, such as dysarthria, dysphagia, gait impairment, falls, and impaired dexterity, are believed to be exacerbated by coexisting cerebellar pathology. Cerebellar pathology may also contribute to cognitive, behavioral, and pseudobulbar manifestations. Our objective was to systematically assess both intracerebellar pathology and cerebrocerebellar connectivity alterations in a genetically stratified cohort of ALS.
Methods
A prospective, multimodal neuroimaging study was conducted to evaluate the longitudinal evolution of intracerebellar pathology and cerebrocerebellar connectivity, using structural and functional measures.
Results
A total of 113 healthy controls and 212 genetically stratified individuals with ALS were included: (1) C9orf72 hexanucleotide carriers (“C9POS”), (2) sporadic patients who tested negative for ALS-associated genetic variants, and (3) intermediate-length CAG trinucleotide carriers in ATXN2 (“ATXN2”). Flocculonodular lobule (padj = 0.014, 95% CI −5.06e-5 to −3.98e-6) and crura (padj = 0.031, 95% CI −1.63e-3 to −5.55e-5) volume reductions were detected at baseline in sporadic patients. Cerebellofrontal and cerebelloparietal structural connectivity impairment was observed in both C9POS and sporadic patients at baseline, and both projections deteriorated further over time in sporadic patients (padj = 0.003, t(249) = 3.04 and padj = 0.05, t(249) = 1.93). Functional cerebelloparietal uncoupling was evident in sporadic patients at baseline (padj = 0.004, 95% CI −0.19 to −0.03). ATXN2 patients exhibited decreased cerebello-occipital functional connectivity at baseline (padj = 0.004, 95% CI −0.63 to −0.06), progressive cerebellotemporal functional disconnection (padj = 0.025, t(199) = −2.26), and progressive flocculonodular lobule degeneration (padj = 0.017, t(249) = −2.24). C9POS patients showed progressive ventral dentate atrophy (padj = 0.007, t(249) = −2.75). The CSTs (padj < 0.001, 95% CI 4.89e-5 to 1.14e-4) and transcallosal interhemispheric fibers (padj < 0.001, 95% CI 5.21e-5 to 1.31e-4) were affected at baseline in C9POS and exhibited rapid degeneration over the 4 time points. The rate of decline in CST and corpus callosum integrity was faster than the rate of cerebrocerebellar disconnection (padj = 0.001, t(190) = 6.93).
Discussion
ALS is associated with accruing intracerebellar disease burden as well as progressive corticocerebellar uncoupling. Contrary to previous suggestions, we have not detected evidence of compensatory structural or functional changes in response to supratentorial degeneration. The contribution of cerebellar disease burden to dysarthria, dysphagia, gait impairment, pseudobulbar affect, and cognitive deficits should be carefully considered in clinical assessments, monitoring, and multidisciplinary interventions.
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© 2024 American Academy of Neurology.
Publication History
Received: December 18, 2023
Accepted: May 9, 2024
Published online: June 20, 2024
Published in print: July 23, 2024
Disclosure
The authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.
Study Funding
This project was sponsored by the Health Research Board Ireland (JPND-Cofund-2-2019-1 & HRB EIA-2017-019). Neuroradiological aspects of this project were also supported by the Agence Nationale de la Recherche (ANR) France (2022-CEREBRALS), the Irish Institute of Clinical Neuroscience (IICN), the EU Joint Programme—Neurodegenerative Disease Research (JPND), Science Foundation Ireland (SFI SP20/SP/8953), the Andrew Lydon scholarship, and the Iris O'Brien Foundation. The genetic analyses of the study were supported by the MND Association (898-792) and Science Foundation Ireland (17/CDA/4737).
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