Motor cortex degeneration correlates with clinical presentation in ALS

Progressive degeneration of the motor cortex correlated with more aggressive clinical presentations among patients with ALS, according to findings from a prospective, longitudinal, multicenter study published in Neurology.

The results provide Class II evidence that N-acetylaspartate metabolite ratios of the motor cortex, as seen with magnetic resonance spectroscopy, correlated with faster disease progression and increased upper motor neuron signals in these patients, the researchers reported.

“Magnetic resonance spectroscopy is able to evaluate cerebral neurochemistry in vivo, providing biomarkers of cerebral degeneration with diagnostic, prognostic and disease monitoring potential,” Daniel Ta, BSc, of the Neuroscience and Mental Health Institute at the University of Alberta, and colleagues wrote. “N-acetylaspartate, a marker of neuronal integrity, is reduced when expressed in absolute terms and as a ratio to other metabolites including creatine (Cr, a marker of energy metabolism), choline (Cho, a marker of membrane turnover) and myo-inositol (Ino, a putative marker of gliosis).”

This reduction in N-acetylaspartate has been observed in motor and extra-motor regions of the brain, including the frontal lobe, according to Ta and colleagues, but longitudinal magnetic resonance spectroscopy studies are limited, with inconsistent results and small sample sizes. There is “a critical need” for data that examine spectroscopy performance in multicenter studies, with the potential for biomarkers obtained from magnetic resonance spectroscopy that can enable clinical trials, the researchers noted.

Ta and colleagues examined progressive cerebral degeneration in patients with ALS through changes in N-acetylaspartate ratios in the motor and prefrontal cortexes within clinical subgroups of ALS. The study included 76 patients with ALS and 59 healthy control participants. They performed serial clinical evaluations and magnetic resonance spectroscopy at baseline, 4 months and 8 months, using a “harmonized” protocol across five different centers.

The researchers quantified N-acetylaspartate ratios in the motor and prefrontal cortexes, classifying patients into subgroups according to disease progression, upper motor neuron signs and cognitive status. They used linear mixed models to make baseline and longitudinal comparisons of N-acetylaspartate metabolite ratios.

Study findings revealed a difference in age among patients with ALS vs. healthy controls (P = .045), where the mean age for patients with ALS was 58.6 years and 55 for healthy control participants, but no significant differences in sex between these groups. A limb was the most common site of onset for patients with ALS.

Patients with ALS exhibited decreased N-acetylaspartate ratios in the motor cortex at baseline, according to the study results (P < .001). Ta and colleagues found that these ratios were lower among patients with faster disease progression and higher numbers of upper motor neuron signs (P < .05).

The researchers observed a longitudinal decrease in N-acetylaspartate ratios in the motor cortex among patients in both the rapidly progressing and increased upper motor neuron burden groups (P < .01 for both). The severity of upper motor neuron signs did not change significantly over time. While N-acetylaspartate ratios were lower in the prefrontal cortex only among patients with cognitive impairment (P < .05), prefrontal cortex metabolites did not change over time, according to the study results.

“[Magnetic resonance spectroscopy] studies in ALS have consistently revealed abnormalities in the motor cortex, demonstrating reductions in [N-acetylaspartate]/Cr6, [N-acetylaspartate]/Cho and [N-acetylaspartate]/Ino. Previously, neurochemical correlates were reported with [disease progression rate] for both [N-acetylaspartate]/Cr29 and [N-acetylaspartate]/Cho in the motor region, which corroborate with the present study findings,” the researchers wrote. “This has also been reported for both motor and extra-motor areas, particularly in frontotemporal regions with respect to the latter.”

Previous evidence demonstrated decreases in fractional anisotropy among patients with ALS who progress quickly compared with patients with ALS who progress slowly along the corticospinal tract and upper frontal lobe, according to the study results. Together, these findings provide evidence “for neuroanatomical correlates of clinical disease progression in ALS,” according to Ta and colleagues.

“Overall, this study shows progressive cerebral degeneration in the motor cortex can be detected in vivo in [patients with ALS] with more aggressive clinical presentations,” the researchers wrote. “These findings underscore the heterogeneity of the disease, providing further biological evidence of variable spatial and temporal cerebral degeneration in [patients with ALS]. This has relevance for clinical trials, to assist with classification of patients into more homogenous cohorts to evaluate disease-modifying interventions.”