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
In brief
Sporadic ALS preferentially attacks GABA, serotonin and kappa-opioid networks; C9orf72 cases also involve glutamate, endocannabinoid and
In a neuroimaging study of 258 ALS patients, brain atrophy patterns aligned with GABA-A α5, serotonin 1a and kappa-opioid receptor maps in sporadic disease, while carriers of the C9orf72 repeat expansion showed additional links to glutamatergic, endocannabinoid and microglial systems. These findings map neurotransmitter-specific vulnerability and suggest new targets for drug development, though longitudinal data were limited by high dropout.
- Journal
- Annals of neurology (Q1)
- Published
- 21 July 2026
- Study design
- Cross-sectional study
- Evidence level
- Level 3, Low (CEBM 3b)
- Authors
- Marlene Tahedl, We Fong Siah, Jasmin Lope, Jennifer C Hengeveld, Mark A Doherty, Russell L McLaughlin, et al.
- PMID
- 42479906
- DOI
- 10.1002/ana.78316
Why clinicians should know about it
- Picked for Anatomy (paper of the day, 22 July 2026): Neurotransmitter mapping relates anatomy to ALS degeneration patterns
Abstract
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. INTERPRETATION: 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.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.