Abstract
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Objectives The pathological changes linked to ALS, an incurable fatal neuromuscular disorder, are glutamatergic neurotoxicity as a result of deficit in glutamate transporter or receptor function and microglia mediated neurotoxicity as a result of enhanced inflammatory response. Human ALS disease expressing a mutation of superoxidase dismutase type 1 (SOD-1) gene provides a direct link for gene-modulated animal models of ALS.
Methods PET imaging studies were conducted of mGluR5 function with [18F]FPEB and inflammatory response with [11C]PBR28 in 4 ALS mice in progression of the disease and 4 age matched control C57/BL6 mice. Anesthetized (1% isoflurane with O2 flow of 1 L/min) mice were injected with mGluR5 ligand (120 µCi i.v.) or with [11C]PBR28 (250 µCi i.v.) and the volumetric dynamic data were acquired for 90 min or 60 min. PET studies were completed with CT imaging. . Locomotor activity was evaluated in free space. SUV of the accumulation was determined at 60-70 min for [18F]FPEB and 20-30 min for [11C]PBR28.
Results In the ALS mice mGluR5 expression was significantly enhanced in the spinal cord as well as in several brain areas related to motor function. Inflammatory response was enhanced in in lungs, hindbrain, brain stem, and in different parts of spinal cord, indicating activated microglia and expression of peripheral benzodiazepine receptors. In these preliminary studies we observed 5-fold higher enhancement of inflammatory response in brain stem and cervical canal in progression of the disease than in modulation of mGluR5 expression in the same areas.
Conclusions These preliminary studies show strong correlation of glutamatergic function and inflammatory response in the ALS -type degeneration. The developed methods and ligands can be directly applied for human studies.
Research Support NIH-NIBIB R01EB012864 to ALB NIH-NIMH91684 to ALB