Patterns of Altered Brain Metabolism in Amyotrophic Lateral Sclerosis (ALS)

Researchers have made a significant breakthrough in understanding the neurodegenerative disease, Amyotrophic Lateral Sclerosis (ALS), by identifying patterns of altered brain metabolism in patients with the condition and in asymptomatic carriers of the C9orf72 mutation. Using a novel magnetic resonance spectroscopic imaging (MRSI) technique, the study found distinct metabolic markers that could serve as biomarkers for the disease. These findings have the potential to revolutionize the diagnosis and treatment of ALS, a devastating disease with limited treatment options.

Key Takeaways:

• The study used a 7T MR scanner to measure brain metabolism in vivo in asymptomatic C9orf72 mutation carriers and patients with ALS.
• Compared to asymptomatic carriers without the C9orf72 mutation, asymptomatic carriers with the mutation showed evidence of neuronal dysfunction, widespread increased membrane breakdown product, and glutamate excitotoxicity.
• Patients with ALS and the C9orf72 mutation had similar neuronal dysfunction and membrane breakdown as asymptomatic carriers with the mutation, but with more severe and widespread glutamate excitotoxicity and increased glycogen precursor.
• ALS Foundation Netherlands acknowledges the significance of this research, stating that it can facilitate the identification of new and personalized drug targets to prevent or treat ALS.
• The study's findings have implications for the development of biomarkers for inclusion or stratification as well as for drug-target engagement in clinical trials.

Statistics:

• 15 asymptomatic family members with the C9orf72 mutation were enrolled in the study, as well as 18 without the mutation, 4 patients with ALS with the mutation, 35 without the mutation, and 25 population-based controls.
• The study found that patients with ALS and the C9orf72 mutation had increased glutamate excitotoxicity (21.4 ± 6.2) compared to expected values.
• The 7T MRSI technique was able to detect evolving patterns of altered brain metabolism in asymptomatic mutation carriers and patients with ALS.
• Lower total adenosine triphosphate/PCr (tATP/PCr) emerged in ALS C9+ patients (0.88 ± 0.14) compared to ALS C9- patients (1.05 ± 0.15).

Sources:

• 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. eBioMedicine, 2025;121:105963.
• NewsRx. Study Results from UMC Utrecht Brain Centre Update Understanding of Amyotrophic Lateral Sclerosis [Patterns of altered in vivo brain metabolism in patients with amyotrophic lateral sclerosis (ALS) and asymptomatic C9orf72 mutation carriers: a ...]. Drug Week. October 31, 2025; p 2699.