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

BACKGROUND

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder which pathology is still largely unclear.

OBJECTIVES

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 [18F]BCPP-EF, [11C]UCB-J, and [11C]SA4503.

METHODS

Sixteen ALS patients (twelve males, mean age: 57.49 ± 12.08 years) and sixteen healthy controls underwent clinical assessment, MRI, and PET imaging with [18F]BCPP-EF, [11C]UCB-J, and [11C]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 (VT) of predefined regions of interest, corrected for partial volume effects, was the primary outcome.

RESULTS

Across the ALS cohort, [18F]BCPP-EF binding was reduced in the amygdala (-13.9 %, F = 4.938 p = 0.034). Moderate/fast progression ALS patients exhibited [18F]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 [11C]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, [18F]BCPP-EF loss in the insular cortex, amygdala, anterior cingulate, and temporal lobe correlated with lower ALSFRS-R scores (p < 0.05).

CONCLUSIONS

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.