Metabolite alterations in the left dorsolateral prefrontal cortex and its association with cognitive assessments in amyotrophic lateral sclerosis: A longitudinal magnetic resonance spectroscopy study

Abstract

Objective: To characterize the longitudinal metabolite profile of the left dorsolateral prefrontal cortex (DLPFC) in amyotrophic lateral sclerosis (ALS) using magnetic resonance spectroscopy (MRS) and to examine its correlation with cognitive assessments.

Methods: Thirteen patients at baseline and ten at follow-up, along with 14 age-, sex-, and handedness-matched healthy controls (HCs), were recruited. Three Tesla with a 64-channel coil, Point-RESolved Spectroscopy (PRESS) sequence (TR=1500 ms and TE=140 ms) was used. Metabolites in the left DLPFC were quantified using LCModel. Cognitive performance and functional impairment were assessed using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) and Revised ALS Functional Rating Scale (ALSFRS-R), respectively. Group comparisons were adjusted for multiple comparisons (p < 0.05, Bonferroni correction). The links between the brain metabolites and cognitive function were investigated using relevant correlation tests (Pearson's or Spearman's).

Results: Our analysis revealed a significant difference in the choline-to-creatine ratio (tCho/tCr) among the three groups. Baseline ALS patients showed a higher tCho/tCr ratio than HCs (p = 0.033, Bonferroni-corrected). Interestingly, the total N-acetyl aspartate (tNAA)/tCr ratio, a marker of neuronal health, was strongly positively correlated with visuospatial cognitive scores at baseline and follow-up. Furthermore, at follow-up, tNAA/tCr was positively correlated with the total scores and specific sub-scores on the ECAS, encompassing both ALS-specific and non-specific cognitive domains. At follow-up, positive correlations emerged between tNAA/tCr and the total language and executive function scores.

Conclusions: Metabolite alterations and correlations with cognition were observed in the left DLPFC of ALS patients, supporting extra-motor involvement and its association with cognitive decline.

Keywords: Amyotrophic Lateral Sclerosis; Biomarker; Brain Metabolite; Dorsolateral Prefrontal Cortex; Magnetic Resonance Spectroscopy.