Patterns of altered in vivo brain metabolism in patients with amyotrophic lateral sclerosis (ALS) and asymptomatic C9orf72 mutation carriers: a cross-sectional ¹H and ³¹P magnetic resonance spectroscopic 7T imaging study

Background: Processes leading to the onset of neurodegeneration in amyotrophic lateral sclerosis (ALS) are largely unknown. To gain insight into disease mechanisms, we measured brain metabolism in vivo in asymptomatic C9orf72 mutation carriers and patients with ALS. Methods: We enroled 15 asymptomatic family members with (AFM C9+) and 18 without a C9orf72 mutation (AFM C9−), 4 patients with ALS with (ALS C9+) and 35 without this mutation (ALS C9−), and 25 population-based controls (CO). Two-dimensional proton (¹H) and whole-brain phosphorus (³¹P) magnetic resonance spectroscopic imaging (MRSI) data were obtained using a 7T MR scanner. 11 brain metabolites were compared between groups using weighted Bayesian linear multilevel models. Findings: Compared to AFM C9−, AFM C9+ showed evidence of neuronal dysfunction (decreased total N-acetyl aspartate/total creatine (tNAA/tCr)), widespread increased membrane breakdown product (glycerol phosphorylethanolamine/phosphocreatine (GPE/PCr)), glutamate excitotoxicity (increased glutamate + glutamine/tNAA (Glx/tNAA)) and, in frontoparietal regions, an increase in the glycogen precursor uridine diphosphoglucose/PCr (UDPG/PCr). Compared to AFM C9+, neuronal dysfunction and membrane breakdown are similar in ALS C9+, but glutamate excitotoxicity and increased glycogen precursor are more severe and widespread, also involving the primary motor region. Moreover, lower total adenosine triphosphate/PCr (tATP/PCr) emerged in ALS C9+, and signs of disturbed membrane synthesis, intracellular second messenger system and glial pathology (myo-inositol + glycine/tCr (mI + Gly/tCr)). ALS C9− is characterised by glutamate excitotoxicity, increased tATP/PCr, and lower phospholipid levels. Interpretation: ¹H and ³¹P 7T MRSI can detect evolving patterns of altered brain metabolism in asymptomatic mutation carriers and patients with ALS. Abnormalities in patients with ALS C9+ appeared to be different from those in patients with ALS C9−. Metabolic markers, measured in vivo, can serve as biomarkers for inclusion or stratification as well as for drug-target engagement in clinical trials. This method can facilitate identification of new and personalised drug targets to prevent or treat this devastating disease. Funding: ALS Foundation Netherlands.