Work

An in vivo PET/CT investigation of mitochondrial complex 1, sigma 1, and synaptic vesicle 2 A in patients with amyotrophic lateral sclerosis

Year: 2025

Type: article

Abstract: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder which pathology is still largely unclear. To perform an in vivo cross-sectional investigation of mitochondrial complex 1 (MC1), synaptic vesicle 2 A (SV2A), and sigma-1 receptor (S1R) expression in ALS patients using the PET radioligands [ 18 F]BCPP-EF, [ 11 C]UCB-J, and [ 11 C]SA4503. Sixteen ALS patients (twelve males, mean age: 57.49 ± 12.08 years) and sixteen healthy controls underwent clinical assessment, MRI, and PET imaging with [ 18 F]BCPP-EF, [ 11 C]UCB-J, and [ 11 C]SA4503. Patients were stratified based on disease the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) progression rate into slow, and moderate/fast progressors. Volume of distribution (V T ) of predefined regions of interest, corrected for partial volume effects, was the primary outcome. Across the ALS cohort, [ 18 F]BCPP-EF binding was reduced in the amygdala (−13.9 %, F = 4.938 p = 0.034). Moderate/fast progression ALS patients exhibited [ 18 F]BCPP-EF binding loss in the hippocampus (−20.0 %), amygdala (−21.4 %), cerebellum (−19.5 %), insular cortex (−19.3 %), temporal lobe (−19.0 %), and anterior cingulate (−18.7 %) (all p < 0.05); and [ 11 C]SA4503 binding loss in the caudate (−20.6 %), pallidus (−26.8 %), amygdala (−20.2 %), hippocampus (−17.4 %), insular cortex (−16.9 %), accumbens (−17.0 %), anterior cingulate (−16.4 %) and temporal lobe (−19.8 %) compared to controls (all p < 0.05). In moderate/fast progressors, [ 18 F]BCPP-EF loss in the insular cortex, amygdala, anterior cingulate, and temporal lobe correlated with lower ALSFRS-R scores ( p < 0.05). Our findings reveal loss of MC1 and S1R in ALS, suggesting mitochondrial dysfunction associated with disease progression. This work provides initial insights of mitochondrial and receptor pathology in ALS, potentially guiding future biomarker development and therapeutic interventions. • Sixteen ALS patients underwent [ 18 F]BCPP-EF, [ 11 C]UCB-J, and [ 11 C]SA4503 PET scans. • The whole ALS group showed a significant [ 18 F]BCPP-EF loss in the amygdala. • A small subset of moderate/fast progressor had [ 18 F]BCPP-EF and [ 11 C]SA4503 loss • In this group, [ 18 F]BCPP-EF loss correlated with higher disease severity. • [ 18 F]BCPP-EF loss correlated with [ 11 C]UCB-J loss in ALS and moderate/fast progressors.

Source: Neurobiology of Disease

DOI: 10.1016/j.nbd.2025.107138