Imaging identifies patterns of cerebral degeneration, associated characteristics in ALS

Heterogeneity of disease phenotype and the C9orf72 genotype correlated with distinct patterns of cerebral degeneration among patients with amyotrophic lateral sclerosis, according to findings published in Neurology.

The study, which used T1-weighted and diffusion-weighted MRI to assess changes in the brain, also showed that imaging studies can be used to track disease progression.

“Amyotrophic lateral sclerosis (ALS) is clinically and genetically a heterogeneous disease,” the researchers wrote. “Up to 15% of patients develop frontotemporal dementia, and another 35% have some degree of cognitive or behavioral impairment. A repeat expansion in C9orf72 appears to be the most common mutation in patients with ALS.”

However, the pathologic mechanisms that underlie neurodegeneration in ALS have not yet been determined, according to the researchers. A greater understanding about how neurodegeneration occurs over time, and about its associated biomarkers in patients with ALS and subgroups based on phenotype or genotype, may help identify therapies to slow or stop disease progression.

Hannelore K. van der Burgh, MSc, of the department of neurology at the UMC Utrecht Brain Center, University Medical Center Utrecht, and colleagues aimed to understand the progressive nature of ALS by examining patterns of gray and white matter involvement in clinically or genetically defined subgroups of patients. The researchers examined cortical thickness, subcortical volumes and white matter connectivity using T1-weighted and diffusion-weighted MRI in patients with ALS and control participants. Linear mixed-effects models assessed changes in structural brain measurements over time in patients compared with control participants.

The analysis included 292 patients with ALS and 156 control participants.

The researchers identified the C9orf72 repeat expansion in 24 patients. Diffusion-weighted imaging data were available for 251 patients with ALS, including 21 C9orf72-positive patients, and 135 control participants. Follow-up data were available for 133 patients with ALS who did not have the C9orf72 repeat expansion and 17 C9orf72-positive patients with ALS. The median follow-up time between the first and second visit was 5.23 months; the relatively short follow-up was because of “the progressive nature of the disease,” according to van der Burgh and colleagues.

Genetic data were available for 211 patients, seven of whom had a pathogenic mutation other than the C9orf72 repeat expansion. In the control group, 72 participants had two or three follow-up visits (median follow-up time, 11.5 months). Participants dropped out at follow-up for the following reasons: they were unable to undergo a second scan (n = 73), were deceased at follow-up (n = 58) or the second scan had not been scheduled yet according to the study protocol at the time of analysis (n = 102).

Patients with a C9orf72 mutation (n = 24) displayed widespread gray and white matter involvement at baseline and extensive loss of white matter integrity in the connectome over time, according to van der Burgh and colleagues. Among C9orf72-negative patients, researchers identified cortical thinning of motor and frontotemporal regions, as well as loss of white matter integrity in connections linked to the motor cortex.

Patients with spinal-onset ALS demonstrated widespread white matter involvement at baseline and gray matter atrophy over time; patients with bulbar onset started out with prominent gray matter involvement. Patients with unchanged cognition or behavior showed predominantly motor system involvement, while extensive cerebral changes – including frontotemporal regions with progressive white matter involvement over time – correlated with impaired behavior or cognition. Progressive loss of gray and white matter integrity typically occurred in patients with shorter disease durations (< 13 months), regardless of progression rate.

“The heterogeneity of our findings among subgroups of patients may have important implications for cross-sectional and follow-up MRI studies in ALS and the timing of neuroimaging in the disease course for clinical trials and follow-up studies,” van der Burgh and colleagues wrote.

They also noted that the study “underlines the potential” of imaging studies to provide researchers with information about structural brain involvement in relation to the heterogeneity of ALS.

“The observed results might indicate that cerebral changes in ALS occur at a relatively early stage of the disease, leastwise at the level at which current multimodal techniques are able to detect abnormalities. This may imply that when designing clinical trials, inclusion of patients at an early stage of the disease is necessary to prevent cerebral neurodegeneration,” the researchers wrote. “These cerebral changes could be monitored by MRI provided that the appropriate modalities are applied to the right subgroups based on phenotypic characteristics or genotype.”