Neuroimaging correlates of domain-specific cognitive deficits in amyotrophic lateral sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with frequent extra-motor involvement. In the present study, we investigated whether specific cognitive and behavioral deficits in ALS correlate with distinct extra-motor neurodegeneration patterns on brain MRI. Methods: We performed multimodal brain MRI and Edinburgh cognitive and behavioral ALS screen (ECAS) in 293 patients and 237 controls. Follow-up data were acquired from 171 patients with a median duration of 7.9 months. Domain-level cognitive scores from the ECAS were compared with grey and white matter MRI parameters. Interaction analyses between patients and controls were performed to explore whether correlates were specific to ALS, rather than related to normal aging. Follow-up data were used to assess changes of domain-associated brain structures over time. Results: Language impairment was significantly associated with (left predominant) frontal, temporal, parietal and subcortical grey matter neurodegeneration. Letter fluency with widespread cortical and subcortical grey matter involvement. Memory dysfunction with hippocampal and medial-temporal atrophy. Executive impairment was exclusively correlated with widespread white matter impairment. Visuospatial scores did not correlate with MRI parameters. Interaction analyses between patients and controls showed that most ECAS-MRI correlations were stronger in ALS than in controls (75.7% significant in grey matter, 52.7% in white matter). Longitudinal analyses showed that all grey matter structures associated with cognitive domains worsened over time while, for this study population, ECAS domain scores did not decline significantly. Conclusions: MRI can capture the heterogeneity of cognitive and behavioral involvement in ALS and provides a useful longitudinal biomarker for progression of extra-motor neurodegeneration.