Progressive Neurochemical Abnormalities in Cognitive and Motor Subgroups of Amyotrophic Lateral Sclerosis: A Prospective Multicenter Study

Abstract

Objective: To evaluate progressive cerebral degeneration in amyotrophic lateral sclerosis (ALS) by assessing alterations in N-acetylaspartate (NAA) ratios in the motor and prefrontal cortex within clinical subgroups of ALS.

Methods: Seventy-six patients with ALS and 59 healthy controls were enrolled in a prospective, longitudinal, multicenter study in the Canadian ALS Neuroimaging Consortium. Participants underwent serial clinical evaluations and magnetic resonance spectroscopy at baseline and 4 and 8 months using a harmonized protocol across 5 centers. NAA ratios were quantified in the motor cortex and prefrontal cortex. Patients were stratified into subgroups based on disease progression rate, upper motor neuron (UMN) signs, and cognitive status. Linear mixed models were used for baseline and longitudinal comparisons of NAA metabolite ratios.

Results: Patients with ALS had reduced NAA ratios in the motor cortex at baseline (p < 0.001). Ratios were lower in those with more rapid disease progression and greater UMN signs (p < 0.05). A longitudinal decline in NAA ratios was observed in the motor cortex in the rapidly progressing (p < 0.01) and high UMN burden (p < 0.01) cohorts. The severity of UMN signs did not change significantly over time. NAA ratios were reduced in the prefrontal cortex only in cognitively impaired patients (p < 0.05); prefrontal cortex metabolites did not change over time.

Conclusions: Progressive degeneration of the motor cortex in ALS is associated with more aggressive clinical presentations. These findings provide biological evidence of variable spatial and temporal cerebral degeneration linked to the disease heterogeneity of ALS. The use of standardized imaging protocols may have a role in clinical trials for patient selection or subgrouping.

Classification of evidence: This study provides Class II evidence that MRS NAA metabolite ratios of the motor cortex are associated with more rapid disease progression and greater UMN signs in patients with ALS.

Trial registration information: ClinicalTrials.gov Identifier: NCT02405182.

© 2021 American Academy of Neurology.

Figures

Figure 1. Single-Voxel MR Spectroscopy and Representative Spectra From the Motor and mPFC

(A) Representative magnetic resonance (MR) spectrum from the (B) motor cortex and (C) an MR spectrum from the (D) mesial prefrontal cortex (mPFC). Cho = choline; Cr = creatine; Ino = myo-inositol; NAA = N-acetylaspartate.

Figure 2. Flow Diagram of Study Participants

Number of participants included in the study at each time point. Reasons for participant withdrawal are included. ALS = amyotrophic lateral sclerosis; HC = healthy control.

Figure 3. Boxplots of Baseline Motor Neurometabolites in Healthy Controls and ALS Patients

Metabolite ratios are adjusted for age, site of acquisition, and percentage of voxel gray matter. Patients are subgrouped according to baseline characteristics of (A) disease progression rate and (B) degree of upper motor neuron (UMN) burden on clinical examination. Statistical analyses were conducted with linear mixed regression to compare groupwise differences. ALS = amyotrophic lateral sclerosis; ALS-FP = fast-progressing ALS; ALS-SP = slowly progressing ALS; ALS-UMNH = ALS with high UMN burden; ALS-UMNL = ALS with low UMN burden; Cho = choline; Cr = creatine; Ino = myo-inositol; NAA = N-acetylaspartate.

Figure 4. Observed Linear Trajectories of Neurometabolite Ratios Over Time for Healthy Controls and ALS Patient Subgroups

Slopes were derived from linear mixed models, accounting for age, site of acquisition, and percentage of voxel grey matter. Trajectories of motor N-acetylaspartate (NAA)/creatine (Cr) and NAA/choline (Cho) decline for (A) patients with amyotrophic lateral sclerosis (ALS) that is fast progressing (ALS-FP) and (B) patients with ALS with high upper motor neuron (UMN) burden (ALS-UMNH) were significantly faster (p < 0.05). Dashed lines = 95% confidence interval. ALS-SP = slowly progressing ALS; ALS-UMNL = ALS with low UMN burden; ns = nonsignificant.