Neurotransmitter-Defined Degeneration Patterns in Sporadic and C9orf72-Associated Amyotrophic Lateral Sclerosis: Predilection to GABAergic, Serotonergic, Opioid, Glutamatergic, Endocannabinoid, and Microglial Systems-Implications for Therapy Development.

Abstract

Amyotrophic lateral sclerosis (ALS) has a markedly distinctive clinical and neuroradiological signature, with the preferential involvement of specific brain networks and the apparent sparing of others. The molecular underpinnings of the strikingly selective anatomical vulnerability have not been fully elucidated to date despite the potential therapeutic relevance of characterizing neurotransmitter receptor-defined susceptibility to degeneration. A large neuroimaging study was undertaken with 258 participants to systematically evaluate topological associations between neurodegeneration and neurotransmitter expression distributions. Patients were stratified based on their genetic profile into sporadic and C90rf72 hexanucleotide repeat expansion carriers. Anatomical associations were evaluated between patterns of atrophy and topological neurotransmitter receptor distributions. Cross-sectional and longitudinal trends were comprehensively evaluated over 4 consecutive timepoints. Our analyses reveal topological associations between neurodegeneration in sporadic ALS and GABA-A receptor α5-selective component (GABAa5), serotonin 1a receptor, and kappa opioid receptor expression maps. In addition to these networks, neuronal loss in patients with GGGGCC hexanucleotide repeat expansions exhibit predilection to glutamatergic, endocannabinoid, and microglial systems. Our multi-timepoint longitudinal analyses reveal dynamic temporal associations between focal volume loss and neurotransmitter expression with increasing spatial associations with noradrenaline transporter and GABAa5, but high attrition rates preclude definite longitudinal inferences. Our data suggest the preferential vulnerability of GABAergic, serotonergic, kappa opioid mediated networks in sporadic ALS. In C9orf72-assocaited ALS, glutamatergic, endocannabinoid circuits are also susceptible and microglia-mediated neuroinflammation is also implicated. The comprehensive evaluation of neurotransmitter-receptor associations not only offer academic insights regarding pathophysiological processes in ALS, but may inform targeted therapy development strategies. ANN NEUROL 2026.