Radiological correlates of pseudobulbar affect: Corticobulbar and cerebellar components in primary lateral sclerosis

Tahedl, Marlene; Tan, Ee Ling; Siah, We Fong; Hengeveld, Jennifer C.; Doherty, Mark A.; McLaughlin, Russell L.; Hardiman, Orla; Finegan, Eoin; Bede, Peter

doi:10.1016/j.jns.2023.120726

Cited by 6 publications

(1 citation statement)

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“…Despite the vast cognitive literature of ALS, 15 neuropsychological deficits are typically solely linked to frontotemporal dysfunction 16 overlooking the physiologic role of the cerebellum in regulating a multitude of cognitive, behavioral, mood, language, and emotional processes. [17][18][19] While pseudobulbar affect is traditionally linked to corticobulbar tract degeneration, 20,21 impaired cerebellar gating is increasingly implicated in its etiology. 22 While the discovery of GGGGCC repeat expansions in C9orf72 cemented the notion of an ALS-frontotemporal dementia (FTD) continuum, the recent identification of repeat expansions in ATXN1 and ATXN2 may indicate the existence of an ALS-ataxia continuum.…”

Section: Introductionmentioning

confidence: 99%

Progressive Cerebrocerebellar Uncoupling in Sporadic and Genetic Forms of Amyotrophic Lateral Sclerosis

Tahedl,

Tan,

Kleinerova

et al. 2024

Neurology

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Background and ObjectivesAmyotrophic 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. MethodsA prospective, multimodal neuroimaging study was conducted to evaluate the longitudinal evolution of intracerebellar pathology and cerebrocerebellar connectivity, using structural and functional measures. ResultsA 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 (p adj = 0.014, 95% CI −5.06e-5 to −3.98e-6) and crura (p adj = 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 (p adj = 0.003, t(249) = 3.04 and p adj = 0.05, t(249) = 1.93). Functional cerebelloparietal uncoupling was evident in sporadic patients at baseline (p adj = 0.004, 95% CI −0.19 to −0.03). ATXN2 patients exhibited decreased cerebello-occipital functional connectivity at baseline (p adj = 0.004, 95% CI −0.63 to −0.06), progressive cerebellotemporal functional disconnection (p adj = 0.025, t(199) = −2.26), and progressive flocculonodular lobule degeneration (p adj = 0.017, t(249) = −2.24). C9POS patients showed progressive ventral dentate atrophy (p adj = 0.007, t(249) = −2.75). The CSTs (p adj < 0.001, 95% CI 4.89e-5 to 1.14e-4) and transcallosal interhemispheric fibers (p adj < 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 (p adj = 0.001, t(190) = 6.93). DiscussionALS 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,

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